FH (P07954) variants and mutations
FH (also known as P07954) is a human protein-coding gene encoding a fumarate hydratase, mitochondrial protein. It converts fumarate to malate in the mitochondrial TCA cycle. Biallelic loss causes fumarase deficiency, while heterozygous loss-of-function variants cause hereditary leiomyomatosis and renal cell cancer syndrome through fumarate accumulation and tumor-suppressor loss. This analysis covers 1,513 FH variants and mutations. Of these, 71% have computational variant effect predictions. Disease context includes hereditary leiomyomatosis and renal cell cancer, fumaric aciduria, and Inherited cancer-predisposing syndrome. Example FH variants include M1I, M1K, and M1L.
Variant analysis overview
- Gene: FH
- Protein: P07954
- UniProt accession: P07954
- Organism: Homo sapiens
- Variants analyzed: 1513
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,362 unspecified-consequence records; 42 missense variants; 81 synonymous variants; 7 frameshift variants; 2 in-frame insertions; 1 stop retained variant; 1 stop lost; 1 stop-gained variants; 1 in-frame deletions; 2 protein altering variant; 4 splice-region variants; 9 substitution
- Prediction scores: 1,076 variants have prediction scores (71% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: hereditary leiomyomatosis and renal cell cancer, fumaric aciduria, Inherited cancer-predisposing syndrome, hereditary neoplastic syndrome, Multiple cutaneous leiomyomas, neurodegenerative disease, tricarboxylic acid cycle disorder, renal carcinoma, ovarian cancer, hereditary pheochromocytoma-paraganglioma, cutaneous melanoma, neuroendocrine carcinoma.
Protein structure and variant hotspots
- Protein features: 6 binding sites; 24 post-translational modification sites.
- PTM context: 35 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable FH variants
Examples include M1I, M1K, M1L, M1R, M1T, M1V, Y2*, Y2C. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1I (p.Met1Ile), rs564147469, ClinGen CA345443120, ClinVar RCV002642166, ClinVar RCV004616956, MetaLR 0.96, MetaSVM 1.06, Conflicting interpretations, not provided
- M1K (p.Met1Lys), rs201261794, ClinGen CA40338164, ClinVar RCV002550252, ClinVar RCV003169938, MetaLR 0.97, MetaSVM 1.06, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- M1L (p.Met1Leu), rs776806414, ClinGen CA1478787, ClinVar RCV000794812, ClinVar RCV002422699, MetaLR 0.96, MetaSVM 1.08, Conflicting interpretations, not provided; Hereditary cancer-predisposing syndrome
- M1R (p.Met1Arg), rs201261794, ClinGen CA345443122, ClinVar RCV000493638, ClinVar RCV002524006, MetaLR 0.97, MetaSVM 1.06, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided; Fumarase deficiency
- M1T (p.Met1Thr), rs201261794, ClinGen CA1478786, ClinVar RCV001017952, ClinVar RCV002551805, MetaLR 0.97, MetaSVM 1.06, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided; Fumarase deficiency
- M1V (p.Met1Val), rs776806414, ClinGen CA10581788, ClinVar RCV000498198, ClinVar RCV002417984, MetaLR 0.96, MetaSVM 1.08, Conflicting interpretations, not provided; Fumarase deficiency; Hereditary leiomyomatosis and renal cell canc
- Y2* (p.Tyr2Ter), rs199971078, ClinGen CA40338139, ClinVar RCV000572622, ClinVar RCV002461294, CADD 36.00, Pathogenic
- Y2C (p.Tyr2Cys), rs1553342167, ClinGen CA345443111, ClinVar RCV002358784, ClinVar RCV002529839, REVEL 0.48, CADD 22.50, Conflicting interpretations, Fumarase deficiency; not provided; Hereditary cancer-predisposing syndrome
- Y2F (p.Tyr2Phe), TOPMed rs1553342167, gnomAD rs1553342167, Likely benign
- Y2H (p.Tyr2His), rs112335468, ClinGen CA1478785, ClinVar RCV001023401, ClinVar RCV001662540, REVEL 0.31, CADD 17.10, Conflicting interpretations, Fumarase deficiency; Inherited phaeochromocytoma and paraganglioma excluding NF1
- Y2N (p.Tyr2Asn), rs112335468, ClinGen CA345443117, ClinVar RCV002547376, ClinVar RCV004035857, REVEL 0.34, CADD 18.30, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R3* (p.Arg3Ter), rs202166344, ClinGen CA321335, ClinVar RCV000196918, ClinVar RCV002415845, CADD 38.00, Pathogenic
- R3G (p.Arg3Gly), rs202166344, ClinGen CA319970, ClinVar RCV000195609, ClinVar RCV000204400, REVEL 0.42, CADD 23.80, Conflicting interpretations, not specified; Hereditary cancer-predisposing syndrome; not provided
- R3P (p.Arg3Pro), rs1573890051, ClinGen CA345443104, ClinVar RCV001018625, ClinVar RCV002549481, AlphaMissense 0.20, MetaLR 0.91, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- R3Q (p.Arg3Gln), rs1573890051, ClinGen CA345443105, ClinVar RCV003841317, ClinVar RCV005567681, REVEL 0.47, AlphaMissense 0.20, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A4E (p.Ala4Glu), rs1252151546, ClinGen CA345443095, ClinVar RCV002348799, ClinVar RCV002563872, REVEL 0.47, CADD 18.50, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A4G (p.Ala4Gly), rs1252151546, ClinGen CA345443093, ClinVar RCV003687739, REVEL 0.34, CADD 14.90, Uncertain significance, not provided
- A4P (p.Ala4Pro), TOPMed rs1573890047, gnomAD rs1573890047, REVEL 0.60, CADD 12.40, Likely benign
- A4S (p.Ala4Ser), TOPMed rs1573890047, gnomAD rs1573890047, Likely benign
- A4T (p.Ala4Thr), rs1573890047, ClinGen CA345443100, ClinVar RCV000804394, ClinVar RCV002534780, REVEL 0.30, CADD 10.20, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- A4V (p.Ala4Val), gnomAD rs1252151546, REVEL 0.32, CADD 15.60, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L5F (p.Leu5Phe), rs1553342165, ClinGen CA345443088, ClinVar RCV000566793, ClinVar RCV004777751, REVEL 0.32, AlphaMissense 0.08, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L5P (p.Leu5Pro), rs200099371, ClinGen CA40338101, ClinVar RCV002388217, ClinVar RCV002544830, REVEL 0.42, AlphaMissense 0.13, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L5R (p.Leu5Arg), rs200099371, ClinGen CA345443084, ClinVar RCV003205407, ClinVar RCV003561228, AlphaMissense 0.13, MetaLR 0.92, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L5V (p.Leu5Val), rs1553342165, ClinGen CA345443090, ClinVar RCV002563802, Ensembl rs1553342165, AlphaMissense 0.08, MetaLR 0.87, Uncertain significance, not provided
- R6G (p.Arg6Gly), rs1660324018, ClinGen CA345443082, ClinVar RCV003339131, ClinVar RCV004572947, REVEL 0.60, CADD 15.20, Uncertain significance, Fumarase deficiency; Hereditary cancer-predisposing syndrome
- R6P (p.Arg6Pro), rs2527345698, ClinGen CA345443078, ClinVar RCV003731926, ClinVar RCV005844294, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R6Q (p.Arg6Gln), rs2527345698, ClinGen CA345443080, ClinVar RCV003047177, REVEL 0.46, CADD 20.60, Uncertain significance, not provided
- R6W (p.Arg6Trp), rs1660324018, ClinGen CA345443081, ClinVar RCV002398023, ClinVar RCV002564442, REVEL 0.39, CADD 17.00, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- L7F (p.Leu7Phe), Ensembl rs2147927073
- L7H (p.Leu7His), Ensembl rs2147927070
- L8F (p.Leu8Phe), rs1660323820, ClinGen CA345443062, ClinVar RCV003810687, ClinVar RCV004366704, REVEL 0.37, CADD 12.10, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L8R (p.Leu8Arg), rs2527345676, ClinGen CA345443057, ClinVar RCV003177557, ClinVar RCV006473866, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- L8V (p.Leu8Val), rs1660323820, ClinGen CA345443063, ClinVar RCV002563737, Ensembl rs1660323820, REVEL 0.38, CADD 11.50, Uncertain significance, not provided
- A9G (p.Ala9Gly), rs766915154, ClinGen CA40338096, ClinVar RCV000562796, ClinVar RCV000635299, REVEL 0.55, CADD 21.90, Conflicting interpretations, Hereditary cancer-predisposing syndrome; Fumarase deficiency; not provided
- A9T (p.Ala9Thr), TOPMed rs1660323710, Uncertain significance, Hereditary cancer-predisposing syndrome
- A9V (p.Ala9Val), TOPMed rs766915154, gnomAD rs766915154, REVEL 0.46, CADD 22.10, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R10C (p.Arg10Cys), rs201507555, ClinGen CA40338083, ClinVar RCV001039209, ClinVar RCV001759736, REVEL 0.54, CADD 23.40, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- R10G (p.Arg10Gly), rs201507555, ClinVar RCV004590611, ClinVar RCV005836651, REVEL 0.54, CADD 21.90, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R10H (p.Arg10His), TOPMed rs1660323387, REVEL 0.53, AlphaMissense 0.43, Uncertain significance, Hereditary cancer-predisposing syndrome
- R10L (p.Arg10Leu), rs1660323387, ClinGen CA345443032, ClinVar RCV002435608, ClinVar RCV005058853, AlphaMissense 0.43, MetaLR 0.88, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- S11* (p.Ser11Ter), rs1226883651, ClinGen CA345443022, ClinVar RCV003461572, ClinVar RCV006473228, AlphaMissense 0.21, MetaLR 0.88, Pathogenic
- S11L (p.Ser11Leu), rs1226883651, ClinGen CA345443018, ClinVar RCV002548719, ClinVar RCV004039748, REVEL 0.35, AlphaMissense 0.21, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- S11P (p.Ser11Pro), rs1660323255, ClinGen CA345443028, ClinVar RCV002560652, ClinVar RCV004571640, REVEL 0.36, CADD 14.70, Uncertain significance, not provided; Hereditary leiomyomatosis and renal cell cancer; Fumarase deficien
- S11W (p.Ser11Trp), rs1226883651, ClinGen CA345443020, NCI-TCGA Cosmic COSV6381, REVEL 0.40, AlphaMissense 0.21, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R12C (p.Arg12Cys), rs199912971, ClinGen CA40338059, ClinVar RCV002339199, ClinVar RCV002551468, REVEL 0.43, AlphaMissense 0.11, Uncertain significance, FH-related disorder; Hereditary cancer-predisposing syndrome; not provided
- R12G (p.Arg12Gly), rs199912971, ClinGen CA345443013, ClinVar RCV002454313, ClinVar RCV002548971, AlphaMissense 0.11, MetaLR 0.89, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R12H (p.Arg12His), rs367826177, ClinGen CA345443006, ClinVar RCV002554321, ESP rs367826177, AlphaMissense 0.12, MetaLR 0.90, Uncertain significance, not provided
- R12L (p.Arg12Leu), rs367826177, ClinGen CA1478782, ClinVar RCV000700942, ClinVar RCV001020691, REVEL 0.37, AlphaMissense 0.12, Conflicting interpretations, Hereditary cancer-predisposing syndrome; Fumarase deficiency; not provided
- R12P (p.Arg12Pro), ESP rs367826177, ExAC rs367826177, TOPMed rs367826177, gnomAD rs367826177, REVEL 0.53, AlphaMissense 0.12, Uncertain significance, Hereditary cancer-predisposing syndrome
- R12S (p.Arg12Ser), rs199912971, ClinGen CA345443012, ClinVar RCV002579595, TOPMed rs199912971, AlphaMissense 0.11, MetaLR 0.89, Uncertain significance, not provided
- P13A (p.Pro13Ala), rs587778360, ClinGen CA159734, ClinVar RCV000121087, ClinVar RCV002354305, REVEL 0.36, CADD 1.54, Uncertain significance, Hereditary cancer-predisposing syndrome; Hereditary leiomyomatosis and renal cel
- P13L (p.Pro13Leu), rs1190505598, ClinGen CA345442989, ClinVar RCV001021388, ClinVar RCV005093209, REVEL 0.29, CADD 6.37, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- P13R (p.Pro13Arg), TOPMed rs1190505598, gnomAD rs1190505598, REVEL 0.33, CADD 4.72, Conflicting interpretations, not provided; Hereditary cancer-predisposing syndrome
- P13S (p.Pro13Ser), rs587778360, ClinGen CA10577692, ClinVar RCV000217403, ClinVar RCV002518291, REVEL 0.33, CADD 3.45, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- P13T (p.Pro13Thr), rs587778360, ClinGen CA40338045, ClinVar RCV000808009, ClinVar RCV002363079, REVEL 0.32, CADD 4.39, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- L14F (p.Leu14Phe), rs981562354, ClinGen CA40338036, ClinVar RCV000635308, ClinVar RCV002325224, REVEL 0.35, AlphaMissense 0.08, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- L14I (p.Leu14Ile), TOPMed rs981562354, gnomAD rs981562354, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L14P (p.Leu14Pro), rs1553342163, ClinGen CA345442977, ClinVar RCV000635314, ClinVar RCV002331135, REVEL 0.40, CADD 15.20, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- L14R (p.Leu14Arg), rs2527345537, ClinGen CA2695200400, ClinVar RCV003461570, Uncertain significance, Fumarase deficiency
- L14V (p.Leu14Val), rs981562354, ClinGen CA345442984, ClinVar RCV003719038, AlphaMissense 0.08, MetaLR 0.88, Uncertain significance, not provided
- V15A (p.Val15Ala), rs1660322018, ClinGen CA345442967, ClinVar RCV001204220, ClinVar RCV002561147, AlphaMissense 0.07, MetaLR 0.88, Uncertain significance, not provided
- V15L (p.Val15Leu), rs1463008959, ClinGen CA345442970, ClinVar RCV003011414, ClinVar RCV003377829, REVEL 0.38, CADD 0.03, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- V15M (p.Val15Met), rs1463008959, ClinGen CA345442971, ClinVar RCV003708924, REVEL 0.35, CADD 0.38, Uncertain significance, not provided
- R16P (p.Arg16Pro), rs762310232, ClinGen CA345442957, ClinVar RCV001023079, ExAC rs762310232, AlphaMissense 0.09, MetaLR 0.88, Uncertain significance, Hereditary cancer-predisposing syndrome
- R16Q (p.Arg16Gln), rs762310232, ClinGen CA1478781, ClinVar RCV003067771, ClinVar RCV005019634, REVEL 0.38, AlphaMissense 0.09, Uncertain significance, Hereditary leiomyomatosis and renal cell cancer; Fumarase deficiency; not provid
- R16W (p.Arg16Trp), rs1324875131, ClinGen CA345442959, ClinVar RCV002334348, ClinVar RCV002533605, REVEL 0.48, CADD 22.30, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A17P (p.Ala17Pro), rs755886213, ClinGen CA1478780, ClinVar RCV000563316, ClinVar RCV002528981, REVEL 0.38, CADD 6.24, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- A17S (p.Ala17Ser), ExAC rs755886213, gnomAD rs755886213, REVEL 0.40, CADD 1.89, Likely benign
- A17T (p.Ala17Thr), ExAC rs755886213, gnomAD rs755886213, Likely benign, not provided
- A17V (p.Ala17Val), rs111548093, ClinGen CA321044, ClinVar RCV000566056, ClinVar RCV001722092, REVEL 0.33, CADD 7.13, Likely benign, Hereditary cancer-predisposing syndrome; Hereditary leiomyomatosis and renal cel
- P18A (p.Pro18Ala), rs1660321288, ClinGen CA345442941, ClinVar RCV002350561, ClinVar RCV002543525, AlphaMissense 0.07, MetaLR 0.88, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- P18L (p.Pro18Leu), rs201887750, ClinGen CA289157, ClinVar RCV000121088, ClinVar RCV000273634, REVEL 0.39, CADD 15.30, Benign/Likely benign, Hereditary leiomyomatosis and renal cell cancer; Fumarase deficiency; Hereditary
- P18Q (p.Pro18Gln), 1000Genomes rs201887750, ESP rs201887750, ExAC rs201887750, TOPMed rs201887750, Benign
- A19T (p.Ala19Thr), rs1194889415, ClinGen CA345442932, ClinVar RCV003481598, gnomAD rs1194889415, REVEL 0.34, CADD 12.20, Uncertain significance, not provided
- A19V (p.Ala19Val), Ensembl rs990315199, REVEL 0.45, CADD 8.66
- A20G (p.Ala20Gly), rs1573889953, ClinGen CA345442917, ClinVar RCV003714806, AlphaMissense 0.12, MetaLR 0.87, Uncertain significance, not provided
- A20P (p.Ala20Pro), rs572324497, ClinGen CA345442920, ClinVar RCV002355701, ClinVar RCV003098046, AlphaMissense 0.11, MetaLR 0.86, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A20S (p.Ala20Ser), rs572324497, ClinGen CA1478778, ClinVar RCV003069979, ClinVar RCV004071884, REVEL 0.36, AlphaMissense 0.11, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- A20T (p.Ala20Thr), rs572324497, ClinGen CA1478777, ClinVar RCV001024665, ClinVar RCV002550899, REVEL 0.37, AlphaMissense 0.11, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- A20V (p.Ala20Val), rs1573889953, ClinGen CA345442915, ClinVar RCV001024776, ClinVar RCV001832358, REVEL 0.36, AlphaMissense 0.12, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A21D (p.Ala21Asp), rs1131691251, ClinGen CA345442900, ClinVar RCV002720686, REVEL 0.33, CADD 10.10, Uncertain significance, not provided
- A21G (p.Ala21Gly), rs1131691251, ClinGen CA345442894, ClinVar RCV000493959, ClinVar RCV003558399, REVEL 0.33, CADD 10.20, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A21P (p.Ala21Pro), rs2147926981, ClinGen CA345442905, ClinVar RCV003020308, AlphaMissense 0.08, MetaLR 0.87, Uncertain significance, not provided
- A21S (p.Ala21Ser), Ensembl rs2147926981
- A21V (p.Ala21Val), rs1131691251, ClinGen CA345442891, ClinVar RCV002268582, ClinVar RCV002361145, REVEL 0.40, CADD 11.20, Uncertain significance, Hereditary cancer-predisposing syndrome; not specified; not provided
- L22* (p.Leu22Ter), rs1031919395, ClinGen CA40338006, ClinVar RCV001025446, ClinVar RCV002508277, AlphaMissense 0.06, MetaLR 0.91, Likely pathogenic
- L22F (p.Leu22Phe), rs2527345394, ClinGen CA345442865, ClinVar RCV003724259, ClinVar RCV005335863, REVEL 0.29, CADD 0.10, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- L22S (p.Leu22Ser), rs1031919395, ClinGen CA345442869, ClinVar RCV002625340, ClinVar RCV004045407, AlphaMissense 0.06, MetaLR 0.91, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- A23T (p.Ala23Thr), rs1573889943, ClinGen CA345442855, ClinVar RCV001025670, ClinVar RCV001827208, REVEL 0.32, CADD 14.30, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- A23V (p.Ala23Val), rs2147926968, ClinGen CA345442837, ClinVar RCV002555419, ClinVar RCV003167101, AlphaMissense 0.12, MetaLR 0.89, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- S24L (p.Ser24Leu), rs587778361, ClinGen CA345442828, ClinVar RCV002370846, Ensembl rs587778361, REVEL 0.37, AlphaMissense 0.19, Uncertain significance, Hereditary cancer-predisposing syndrome
- S24T (p.Ser24Thr), rs2527345375, ClinGen CA345442836, ClinVar RCV002715741, ClinVar RCV004067679, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- S24W (p.Ser24Trp), rs587778361, ClinGen CA159737, ClinVar RCV000121089, Ensembl rs587778361, AlphaMissense 0.19, MetaLR 0.89, not provided, not specified
- A25D (p.Ala25Asp), rs1573889933, ClinGen CA345442822, ClinVar RCV003339130, AlphaMissense 0.09, MetaLR 0.88, Uncertain significance, Hereditary cancer-predisposing syndrome
- A25P (p.Ala25Pro), rs999146815, ClinGen CA40337987, ClinVar RCV003880673, ClinVar RCV004621944, REVEL 0.40, CADD 9.89, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- A25S (p.Ala25Ser), NCI-TCGA Cosmic COSV6381, REVEL 0.40, CADD 5.63, Variant assessed as somatic; moderate impact.
- A25T (p.Ala25Thr), rs999146815, ClinGen CA345442825, ClinVar RCV001026389, ClinVar RCV001243101, REVEL 0.37, CADD 7.72, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome; Fumarase deficiency
- A25V (p.Ala25Val), rs1573889933, ClinGen CA345442817, ClinVar RCV002534700, ClinVar RCV005831672, REVEL 0.35, AlphaMissense 0.09, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- P26L (p.Pro26Leu), rs187226800, ClinGen CA289160, ClinVar RCV000121090, ClinVar RCV000227292, REVEL 0.39, CADD 18.20, Benign/Likely benign, Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer; Hereditary
- G27A (p.Gly27Ala), rs1339215584, ClinGen CA345442784, ClinVar RCV002422500, ClinVar RCV002532214, REVEL 0.42, CADD 9.13, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- G27D (p.Gly27Asp), gnomAD rs1339215584, Uncertain significance
- G27R (p.Gly27Arg), NCI-TCGA TCGA novel, Ensembl rs2147926940, Variant assessed as somatic; moderate impact.
- G27V (p.Gly27Val), gnomAD rs1339215584, Uncertain significance
- L28F (p.Leu28Phe), Ensembl rs2147926933, Uncertain significance, not provided
- L28W (p.Leu28Trp), rs2527345107, ClinGen CA345442772, ClinVar RCV003560341, Uncertain significance, not provided
- G29S (p.Gly29Ser), rs2527345089, ClinGen CA345442760, ClinVar RCV004520615, Likely benign, Hereditary cancer-predisposing syndrome
- G29V (p.Gly29Val), rs2147926930, ClinGen CA345442742, ClinVar RCV002373419, ClinVar RCV006620543, REVEL 0.37, CADD 14.10, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- G30D (p.Gly30Asp), rs2147926924, ClinGen CA345442737, ClinVar RCV003341994, ClinVar RCV003708776, AlphaMissense 0.10, MetaLR 0.89, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- A31E (p.Ala31Glu), rs876659347, ClinGen CA345442727, ClinVar RCV002539537, ClinVar RCV005841762, AlphaMissense 0.12, MetaLR 0.89, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A31T (p.Ala31Thr), rs2147926921, ClinGen CA345442732, ClinVar RCV002371237, Ensembl rs2147926921, REVEL 0.28, CADD 5.80, Uncertain significance, Hereditary cancer-predisposing syndrome
- A31V (p.Ala31Val), rs876659347, ClinGen CA10577691, ClinVar RCV000219137, ClinVar RCV002519693, REVEL 0.39, AlphaMissense 0.12, Uncertain significance, Hereditary cancer-predisposing syndrome; not specified; not provided
- A32G (p.Ala32Gly), rs2147926910, ClinGen CA345442722, ClinVar RCV002274525, Ensembl rs2147926910, AlphaMissense 0.10, MetaLR 0.89, Uncertain significance, not provided
- A32P (p.Ala32Pro), rs1371664717, ClinGen CA345442724, ClinVar RCV003736304, AlphaMissense 0.09, MetaLR 0.87, Uncertain significance, not provided
- A32S (p.Ala32Ser), rs1371664717, ClinGen CA345442723, ClinVar RCV000569300, ClinVar RCV002530338, REVEL 0.38, AlphaMissense 0.09, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- A32T (p.Ala32Thr), rs1371664717, ClinGen CA345442725, ClinVar RCV001019431, ClinVar RCV003769514, REVEL 0.37, AlphaMissense 0.09, Uncertain significance, not provided; FH-related disorder; Hereditary cancer-predisposing syndrome
- A32V (p.Ala32Val), rs2147926910, ClinGen CA345442720, ClinVar RCV002553578, ClinVar RCV004946833, AlphaMissense 0.10, MetaLR 0.89, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- V33G (p.Val33Gly), rs1319755767, ClinGen CA345442710, ClinVar RCV000562224, ClinVar RCV001046087, REVEL 0.37, CADD 5.80, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- V33M (p.Val33Met), ExAC rs765041223, REVEL 0.33, CADD 1.20
- P34L (p.Pro34Leu), rs1398860901, ClinGen CA345442702, ClinVar RCV002256895, ClinVar RCV002551222, REVEL 0.24, CADD 10.10, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- P34S (p.Pro34Ser), rs1191023697, ClinGen CA345442706, ClinVar RCV001280071, ClinVar RCV002436991, REVEL 0.28, CADD 2.04, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- S35L (p.Ser35Leu), rs942065027, ClinGen CA345442696, ClinVar RCV001760354, ClinVar RCV002402840, REVEL 0.25, CADD 12.00, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome; not specified
- S35P (p.Ser35Pro), rs1573889890, ClinGen CA345442700, ClinVar RCV002534772, Ensembl rs1573889890, AlphaMissense 0.06, MetaLR 0.90, Uncertain significance, not provided
- S35W (p.Ser35Trp), rs942065027, ClinGen CA40337936, ClinVar RCV001017127, ClinVar RCV001574592, REVEL 0.35, CADD 16.40, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- F36V (p.Phe36Val), rs2147926878, ClinGen CA345442689, ClinVar RCV002269161, ClinVar RCV005565220, AlphaMissense 0.08, MetaLR 0.87, Uncertain significance, Hereditary cancer-predisposing syndrome; not specified
- W37C (p.Trp37Cys), rs1573889881, ClinGen CA345442670, ClinVar RCV001009917, Ensembl rs1573889881, AlphaMissense 0.20, MetaLR 0.91, Uncertain significance, Hereditary cancer-predisposing syndrome
- W37R (p.Trp37Arg), TOPMed rs1660318303
- W37S (p.Trp37Ser), rs1660318244, ClinGen CA345442675, ClinVar RCV003104040, ClinVar RCV004035957, AlphaMissense 0.09, MetaLR 0.92, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- P38A (p.Pro38Ala), Ensembl rs2147926866, Uncertain significance
- P38L (p.Pro38Leu), rs2147926864, ClinGen CA345442660, ClinVar RCV002561380, ClinVar RCV005614726, AlphaMissense 0.09, MetaLR 0.88, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- P38S (p.Pro38Ser), rs2147926866, ClinGen CA345442663, ClinVar RCV002730208, Ensembl rs2147926866, AlphaMissense 0.06, MetaLR 0.87, Uncertain significance, not provided
- P39A (p.Pro39Ala), Ensembl rs2147926857, REVEL 0.41, AlphaMissense 0.07, Uncertain significance
- P39L (p.Pro39Leu), rs1415259326, ClinGen CA345442654, ClinVar RCV002331543, ClinVar RCV002569223, REVEL 0.40, CADD 15.10, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome; Fumarase deficiency
- P39Q (p.Pro39Gln), TOPMed rs1415259326, gnomAD rs1415259326, Uncertain significance
- P39R (p.Pro39Arg), TOPMed rs1415259326, gnomAD rs1415259326, REVEL 0.42, CADD 14.80, Uncertain significance
- P39S (p.Pro39Ser), rs2147926857, ClinGen CA345442657, ClinVar RCV002545744, Ensembl rs2147926857, AlphaMissense 0.07, MetaLR 0.90, Uncertain significance, not provided
- N40K (p.Asn40Lys), rs876658186, ClinGen CA40337913, ClinVar RCV001010297, ClinVar RCV001037079, REVEL 0.23, CADD 19.20, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- A41S (p.Ala41Ser), Ensembl rs2147926842
- A41T (p.Ala41Thr), rs2147926842, ClinGen CA345442643, ClinVar RCV002353969, REVEL 0.35, CADD 11.80, Uncertain significance, Hereditary cancer-predisposing syndrome
- A41V (p.Ala41Val), rs201486221, ClinGen CA189176, ClinVar RCV000163787, ClinVar RCV000342312, REVEL 0.33, CADD 18.90, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not specified; not provided
- A42S (p.Ala42Ser), rs2147926832, ClinGen CA345442634, ClinVar RCV002552917, ClinVar RCV004946823, AlphaMissense 0.07, MetaLR 0.89, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- A42T (p.Ala42Thr), rs2147926832, ClinGen CA345442632, ClinVar RCV002603850, Ensembl rs2147926832, AlphaMissense 0.07, MetaLR 0.89, Uncertain significance, not provided
- A42V (p.Ala42Val), rs1194980336, ClinGen CA345442627, ClinVar RCV003103968, gnomAD rs1194980336, AlphaMissense 0.10, MetaLR 0.89, Uncertain significance, not provided
- R43* (p.Arg43Ter), rs200496951, ClinGen CA40337895, ClinVar RCV001784418, ClinVar RCV003467368, CADD 37.00, Likely pathogenic
- R43G (p.Arg43Gly), rs200496951, ClinGen CA345442626, ClinVar RCV000537507, ClinVar RCV002384077, REVEL 0.45, CADD 23.30, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided; Fumarase deficiency
- R43L (p.Arg43Leu), rs2147926825, ClinGen CA345442622, ClinVar RCV002552865, Ensembl rs2147926825, REVEL 0.55, AlphaMissense 0.17, Uncertain significance, not provided
- R43P (p.Arg43Pro), rs2147926825, ClinGen CA345442623, ClinVar RCV003165111, Ensembl rs2147926825, AlphaMissense 0.17, MetaLR 0.90, Uncertain significance, Hereditary cancer-predisposing syndrome
- M44I (p.Met44Ile), rs863223982, ClinGen CA323363, ClinVar RCV000561722, ClinVar RCV002515400, AlphaMissense 0.38, MetaLR 0.91, Pathogenic, Hereditary cancer-predisposing syndrome; not provided
- M44R (p.Met44Arg), TOPMed rs1296948655, gnomAD rs1296948655
- M44T (p.Met44Thr), TOPMed rs1296948655, gnomAD rs1296948655, REVEL 0.46, CADD 24.20, Uncertain significance, not provided
- A45G (p.Ala45Gly), rs2527340466, ClinGen CA345442065, ClinVar RCV004520587, ClinVar RCV005618355, Uncertain significance, Hereditary cancer-predisposing syndrome
- A45S (p.Ala45Ser), rs1260007300, ClinGen CA345442071, ClinVar RCV001010940, ClinVar RCV002549331, AlphaMissense 0.08, MetaLR 0.91, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided; Fumarase deficiency
- A45T (p.Ala45Thr), NCI-TCGA TCGA novel, gnomAD rs1260007300, REVEL 0.55, AlphaMissense 0.08, Uncertain significance
- S46R (p.Ser46Arg), rs1211942353, NCI-TCGA Cosmic COSV1008, gnomAD rs1211942353, REVEL 0.70, CADD 22.40, Uncertain significance, not provided
- Q47* (p.Gln47Ter), rs863223980, ClinGen CA324825, ClinVar RCV000200269, ClinVar RCV000445602, Pathogenic
- N48I (p.Asn48Ile), rs1660246440, ClinGen CA345442031, ClinVar RCV002560432, ClinVar RCV005343155, REVEL 0.55, AlphaMissense 0.18, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- N48S (p.Asn48Ser), rs1660246440, ClinGen CA345442034, ClinVar RCV002394330, AlphaMissense 0.18, MetaLR 0.91, Uncertain significance, Hereditary cancer-predisposing syndrome
- S49F (p.Ser49Phe), rs1200934499, NCI-TCGA Cosmic COSV6381, TOPMed rs1200934499, gnomAD rs1200934499, REVEL 0.55, CADD 24.80, Variant assessed as somatic; moderate impact.
- F50L (p.Phe50Leu), rs1558402284, ClinGen CA345442019, ClinVar RCV002560740, ClinVar RCV004042049, REVEL 0.55, CADD 24.80, Uncertain significance, not provided
- F50S (p.Phe50Ser), Ensembl rs2147925286, REVEL 0.62, CADD 23.30, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- R51P (p.Arg51Pro), rs976734433, ClinGen CA345442006, ClinVar RCV000797723, ClinVar RCV002537051, AlphaMissense 0.95, MetaLR 0.98, Likely pathogenic, not provided; Hereditary cancer-predisposing syndrome
- R51Q (p.Arg51Gln), rs976734433, ClinGen CA40336041, ClinVar RCV002398014, ClinVar RCV002564404, REVEL 0.93, AlphaMissense 0.95, Pathogenic/Likely pathogenic, Hereditary cancer-predisposing syndrome; not provided
- R51W (p.Arg51Trp), rs778678782, ClinGen CA1478759, ClinVar RCV000804384, ClinVar RCV002256525, REVEL 0.80, CADD 28.00, Conflicting interpretations, Hereditary cancer-predisposing syndrome; Fumarase deficiency; Hereditary leiomyo
- I52L (p.Ile52Leu), rs543844061, ClinGen CA1478757, ClinVar RCV000565315, ClinVar RCV001273185, REVEL 0.45, AlphaMissense 0.06, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- I52V (p.Ile52Val), rs543844061, ClinGen CA345442002, ClinVar RCV002567915, ClinVar RCV003380923, AlphaMissense 0.06, MetaLR 0.88, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- E53* (p.Glu53Ter), rs863224013, ClinGen CA16609380, ClinVar RCV000445623, ClinVar RCV001529890, AlphaMissense 0.99, MetaLR 0.97, Pathogenic
- E53K (p.Glu53Lys), rs863224013, ClinGen CA322588, ClinVar RCV002399736, ClinVar RCV002517215, REVEL 0.90, AlphaMissense 0.99, Conflicting interpretations, Hereditary cancer-predisposing syndrome; not provided
- Y54C (p.Tyr54Cys), rs1270054582, ClinGen CA345441980, ClinVar RCV004520593, TOPMed rs1270054582, REVEL 0.58, CADD 22.00, Uncertain significance, Hereditary cancer-predisposing syndrome
- Y54F (p.Tyr54Phe), TOPMed rs1270054582, REVEL 0.41, CADD 18.90, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- D55N (p.Asp55Asn), rs1660245455, ClinGen CA345441974, ClinVar RCV001216082, Ensembl rs1660245455, AlphaMissense 1.00, MetaLR 0.97, Uncertain significance, Fumarase deficiency
- D55G (p.Asp55Gly), rs1660245400, ClinGen CA345441969, ClinVar RCV002563200, Ensembl rs1660245400, AlphaMissense 1.00, MetaLR 0.97, Uncertain significance, not provided
- D55Y (p.Asp55Tyr), rs1660245455, ClinGen CA345441972, ClinVar RCV003677468, AlphaMissense 1.00, MetaLR 0.97, Uncertain significance, not provided
- T56A (p.Thr56Ala), rs1232573732, ClinGen CA345441963, ClinVar RCV002528877, ClinVar RCV003352953, REVEL 0.59, CADD 21.90, Uncertain significance, not provided; not specified; Hereditary cancer-predisposing syndrome
- T56I (p.Thr56Ile), rs1433872618, ClinGen CA345441961, ClinVar RCV001012693, ClinVar RCV002551761, AlphaMissense 0.35, MetaLR 0.91, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- T56N (p.Thr56Asn), rs1433872618, ClinGen CA345441955, ClinVar RCV002560389, ClinVar RCV005834103, REVEL 0.67, AlphaMissense 0.35, Uncertain significance, not provided; Hereditary cancer-predisposing syndrome
- T56S (p.Thr56Ser), rs1433872618, ClinGen CA345441960, ClinVar RCV001012692, ClinVar RCV002549374, REVEL 0.50, AlphaMissense 0.35, Uncertain significance, Hereditary cancer-predisposing syndrome
- F57S (p.Phe57Ser), rs759884607, ClinGen CA1478755, ClinVar RCV002546810, ClinVar RCV006391920, REVEL 0.91, CADD 26.60, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- G58C (p.Gly58Cys), TOPMed rs11545659, Uncertain significance
- G58D (p.Gly58Asp), rs2527340376, ClinGen CA345441935, ClinVar RCV002407484, ClinVar RCV005058684, REVEL 0.97, CADD 24.40, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
- G58S (p.Gly58Ser), rs11545659, ClinGen CA345441941, ClinVar RCV001012881, ClinVar RCV001731888, REVEL 0.96, CADD 25.90, Uncertain significance, Hereditary cancer-predisposing syndrome; not provided
Public FH analysis runs
- FH analysis run — FH (1,513 variants) — completed 2026-08-18