HMGCS2 (P54868) variants and mutations
HMGCS2 (also known as P54868) is a human protein-coding gene encoding a hydroxymethylglutaryl-CoA synthase, mitochondrial protein. It catalyzes the rate-limiting mitochondrial step of ketone-body synthesis, allowing the liver to convert fatty-acid-derived acetyl-CoA into ketones during fasting. Biallelic deficiency causes impaired ketogenesis with fasting hypoglycemia and potentially severe metabolic decompensation. This analysis covers 853 HMGCS2 variants and mutations. Of these, 78% have computational variant effect predictions. Disease context includes 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, hereditary disease, and hepatocellular carcinoma. Example HMGCS2 variants include R3C, R3G, and R3H.
Variant analysis overview
- Gene: HMGCS2
- Protein: P54868
- UniProt accession: P54868
- Organism: Homo sapiens
- Variants analyzed: 853
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 661 unspecified-consequence records; 1 stop lost; 80 synonymous variants; 74 missense variants; 5 stop-gained variants; 1 in-frame insertions; 18 frameshift variants; 3 in-frame deletions; 7 splice-region variants; 3 substitution
- Prediction scores: 663 variants have prediction scores (78% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, hereditary disease, hepatocellular carcinoma, neoplasm, metabolic dysfunction-associated steatotic liver disease, colorectal carcinoma, posterior cortical atrophy, cancer, esophageal squamous cell carcinoma, acute kidney injury, pulmonary fibrosis, metabolic dysfunction-associated steatohepatitis.
Protein structure and variant hotspots
- Protein features: 10 binding sites; 28 post-translational modification sites.
- PTM context: 26 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, MaveDB, LitVar.
Notable HMGCS2 variants
Examples include R3C, R3G, R3H, T6I, P7A, P7Q, V8A, V8M. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- R3C (p.Arg3Cys), ExAC rs750380692, TOPMed rs750380692, gnomAD rs750380692, REVEL 0.53, CADD 25.60
- R3G (p.Arg3Gly), ExAC rs750380692, TOPMed rs750380692, gnomAD rs750380692, REVEL 0.51, CADD 23.30
- R3H (p.Arg3His), rs72695184, ClinGen CA1038003, cosmic curated COSV10468, ClinVar RCV000815725, REVEL 0.44, CADD 24.40, Uncertain significance, not provided; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- T6I (p.Thr6Ile), TOPMed rs1189194662, gnomAD rs1189194662, REVEL 0.24, CADD 22.10
- P7A (p.Pro7Ala), rs757083410, ExAC rs757083410, gnomAD rs757083410, REVEL 0.27, CADD 17.10, Variant assessed as somatic; moderate impact.
- P7Q (p.Pro7Gln), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, REVEL 0.41, CADD 21.20, Variant assessed as somatic; moderate impact.
- V8A (p.Val8Ala), gnomAD rs1452551580, REVEL 0.11, CADD 8.77
- V8M (p.Val8Met), Ensembl rs2101283706
- K9R (p.Lys9Arg), rs144004292, ClinGen CA1037999, ClinVar RCV000289757, ClinVar RCV005572295, REVEL 0.13, CADD 11.00, Conflicting interpretations, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; Inborn genetic diseases
- R10C (p.Arg10Cys), rs373202578, ClinGen CA30281847, cosmic curated COSV10102, ClinVar RCV004399672, REVEL 0.26, CADD 14.90, Uncertain significance, Inborn genetic diseases
- R10H (p.Arg10His), rs766960590, ExAC rs766960590, gnomAD rs766960590, REVEL 0.26, CADD 3.48, Variant assessed as somatic; moderate impact.
- R10S (p.Arg10Ser), rs373202578, ClinGen CA1037998, ClinVar RCV002756766, ClinVar RCV003274028, REVEL 0.16, CADD 11.90, Uncertain significance, Inborn genetic diseases; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- I11L (p.Ile11Leu), Ensembl rs1653326072, REVEL 0.18, CADD 8.05
- L12P (p.Leu12Pro), rs939049952, ClinGen CA16603380, NCI-TCGA Cosmic COSV6556, cosmic curated COSV65569, REVEL 0.47, CADD 22.40, Uncertain significance, not provided
- L12Q (p.Leu12Gln), rs939049952, ClinGen CA341869767, ClinVar RCV001911824, TOPMed rs939049952, REVEL 0.43, CADD 22.20, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- L12V (p.Leu12Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L14P (p.Leu14Pro), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65569, Variant assessed as somatic; moderate impact.
- T15I (p.Thr15Ile), TOPMed rs1008466802, gnomAD rs1008466802
- T15R (p.Thr15Arg), TOPMed rs1008466802, gnomAD rs1008466802, REVEL 0.15, CADD 0.62
- T15S (p.Thr15Ser), gnomAD rs1286736541, REVEL 0.18, CADD 6.88
- R16K (p.Arg16Lys), ExAC rs773898985, TOPMed rs773898985, gnomAD rs773898985, REVEL 0.07, CADD 4.09
- R16T (p.Arg16Thr), ExAC rs773898985, TOPMed rs773898985, gnomAD rs773898985
- A17E (p.Ala17Glu), 1000Genomes rs587712415, ExAC rs587712415, TOPMed rs587712415, gnomAD rs587712415, REVEL 0.22, CADD 0.16, Uncertain significance
- A17V (p.Ala17Val), rs587712415, ClinGen CA1037994, NCI-TCGA Cosmic COSV6556, cosmic curated COSV65568, REVEL 0.19, CADD 0.03, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- Q19H (p.Gln19His), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, Variant assessed as somatic; moderate impact.
- Q19R (p.Gln19Arg), rs2101283600, ClinGen CA341869634, ClinVar RCV001931383, Ensembl rs2101283600, REVEL 0.06, CADD 8.00, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- E20K (p.Glu20Lys), cosmic curated COSV65567, gnomAD rs1332746126, REVEL 0.11, CADD 12.10
- E20Q (p.Glu20Gln), gnomAD rs1332746126, REVEL 0.06, CADD 10.80
- L23P (p.Leu23Pro), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, Variant assessed as somatic; moderate impact.
- T24I (p.Thr24Ile), rs369221781, ClinGen CA1037990, ClinVar RCV000706394, ESP rs369221781, REVEL 0.22, CADD 8.41, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- P25A (p.Pro25Ala), rs144744634, ClinGen CA312636, ClinVar RCV000185971, ClinVar RCV000647361, REVEL 0.13, CADD 16.10, Conflicting interpretations, not specified; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- P25H (p.Pro25His), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, NCI-TCGA Cosmic COSV6556, Variant assessed as somatic; moderate impact.
- P25L (p.Pro25Leu), NCI-TCGA Cosmic COSV1010, NCI-TCGA Cosmic COSV6556, cosmic curated COSV65569, Variant assessed as somatic; moderate impact.
- P25S (p.Pro25Ser), rs144744634, ClinGen CA341869470, ClinVar RCV001999114, ESP rs144744634, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- A26D (p.Ala26Asp), TOPMed rs1653322892
- A26T (p.Ala26Thr), TOPMed rs893820165, gnomAD rs893820165, REVEL 0.07, CADD 12.10, Uncertain significance, Inborn genetic diseases
- R27C (p.Arg27Cys), rs376238143, ClinGen CA1037987, cosmic curated COSV10102, ClinVar RCV002932141, REVEL 0.30, CADD 16.70, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- R27H (p.Arg27His), rs757169217, NCI-TCGA Cosmic COSV6556, ExAC rs757169217, TOPMed rs757169217, REVEL 0.09, CADD 11.00, Variant assessed as somatic; moderate impact.
- L28P (p.Leu28Pro), gnomAD rs1653322600, REVEL 0.46, CADD 21.40
- P30A (p.Pro30Ala), rs202069145, ClinGen CA1037984, ClinVar RCV000381823, ClinVar RCV002519380, REVEL 0.12, CADD 16.80, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; not provided; Inborn genetic
- P30S (p.Pro30Ser), 1000Genomes rs202069145, ExAC rs202069145, TOPMed rs202069145, gnomAD rs202069145, REVEL 0.12, CADD 18.70, Uncertain significance
- V31A (p.Val31Ala), TOPMed rs1233603916, gnomAD rs1233603916
- V31E (p.Val31Glu), TOPMed rs1233603916, gnomAD rs1233603916, REVEL 0.18, CADD 10.90
- V31I (p.Val31Ile), gnomAD rs1244351356, REVEL 0.24, CADD 8.23
- A32T (p.Ala32Thr), ExAC rs755897068, gnomAD rs755897068, REVEL 0.07, CADD 10.30
- A32V (p.Ala32Val), rs199651321, ClinGen CA1037982, ClinVar RCV000348168, ClinVar RCV002519379, REVEL 0.06, CADD 11.80, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; Inborn genetic diseases
- H33L (p.His33Leu), ExAC rs759183803, gnomAD rs759183803, REVEL 0.23, CADD 13.20
- R35G (p.Arg35Gly), rs1653321576, ClinGen CA341869304, ClinVar RCV001299698, ClinVar RCV006372469, Uncertain significance, Inborn genetic diseases; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- R35K (p.Arg35Lys), ExAC rs751101083, TOPMed rs751101083, gnomAD rs751101083, REVEL 0.17, CADD 19.40, Uncertain significance
- R35M (p.Arg35Met), rs751101083, ClinGen CA1037979, ClinVar RCV000799471, ExAC rs751101083, REVEL 0.36, CADD 21.60, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- R35S (p.Arg35Ser), gnomAD rs1231210408, REVEL 0.19, CADD 22.50
- R35T (p.Arg35Thr), ExAC rs751101083, TOPMed rs751101083, gnomAD rs751101083, REVEL 0.19, CADD 22.50, Uncertain significance
- T38I (p.Thr38Ile), gnomAD rs1282393883, REVEL 0.25, CADD 18.80
- T38K (p.Thr38Lys), cosmic curated COSV65568, gnomAD rs1282393883
- T38P (p.Thr38Pro), Ensembl rs77241754
- A39T (p.Ala39Thr), gnomAD rs1208729772
- S40Y (p.Ser40Tyr), rs1346871356, ClinGen CA341867393, ClinVar RCV002669454, TOPMed rs1346871356, REVEL 0.27, CADD 19.10, Uncertain significance, Inborn genetic diseases
- V42F (p.Val42Phe), ESP rs375279621, ExAC rs375279621, TOPMed rs375279621, gnomAD rs375279621, REVEL 0.16, CADD 14.30
- V42I (p.Val42Ile), ESP rs375279621, ExAC rs375279621, TOPMed rs375279621, gnomAD rs375279621, REVEL 0.15, CADD 9.33
- P43L (p.Pro43Leu), ExAC rs771019602, gnomAD rs771019602, REVEL 0.28, CADD 22.50
- L44P (p.Leu44Pro), ExAC rs749336738, gnomAD rs749336738, REVEL 0.28, CADD 20.50
- K46E (p.Lys46Glu), Ensembl rs1653157137
- T47K (p.Thr47Lys), TOPMed rs1653157007, gnomAD rs1653157007, REVEL 0.26, CADD 17.90
- T47R (p.Thr47Arg), TOPMed rs1653157007, gnomAD rs1653157007
- D48H (p.Asp48His), Ensembl rs199670317, REVEL 0.21, CADD 22.60
- T49I (p.Thr49Ile), rs756404916, ClinGen CA1037947, ClinVar RCV001232384, ExAC rs756404916, REVEL 0.14, CADD 16.70, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- W50* (p.Trp50Ter), Ensembl rs866803752, CADD 37.00
- P51A (p.Pro51Ala), TOPMed rs1653156396
- P51S (p.Pro51Ser), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, REVEL 0.86, CADD 26.20, Variant assessed as somatic; moderate impact.
- D53G (p.Asp53Gly), rs2464283650, ClinGen CA341867109, ClinVar RCV002633795, REVEL 0.86, CADD 26.90, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- V54M (p.Val54Met), rs28937320, ClinGen CA120262, NCI-TCGA Cosmic COSV6556, cosmic curated COSV65567, REVEL 0.88, CADD 25.30, Likely pathogenic, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- G55D (p.Gly55Asp), rs2464283434, ClinGen CA341867051, ClinVar RCV003391156, REVEL 0.91, CADD 25.40, Likely pathogenic, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- G55S (p.Gly55Ser), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, NCI-TCGA Cosmic COSV6556, Variant assessed as somatic; moderate impact.
- A58V (p.Ala58Val), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65569, Variant assessed as somatic; moderate impact.
- L59M (p.Leu59Met), rs181428774, ClinGen CA1037943, ClinVar RCV000756247, ClinVar RCV001099374, REVEL 0.21, CADD 8.64, Conflicting interpretations, not provided; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- L59Q (p.Leu59Gln), TOPMed rs1653154898
- V61A (p.Val61Ala), ExAC rs779833095, REVEL 0.76, CADD 26.00
- V61F (p.Val61Phe), ExAC rs746685363, gnomAD rs746685363, REVEL 0.67, CADD 24.30, Uncertain significance, Inborn genetic diseases
- V61G (p.Val61Gly), rs779833095, ClinGen CA341866942, ClinVar RCV002825692, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- F63L (p.Phe63Leu), ExAC rs758019802, TOPMed rs758019802, gnomAD rs758019802, REVEL 0.64, CADD 23.70
- P64L (p.Pro64Leu), gnomAD rs1185689932, REVEL 0.96, CADD 28.00
- A65D (p.Ala65Asp), TOPMed rs1485324823, gnomAD rs1485324823, REVEL 0.55, CADD 26.20
- A65G (p.Ala65Gly), TOPMed rs1485324823, gnomAD rs1485324823, REVEL 0.31, CADD 22.90
- Q66K (p.Gln66Lys), TOPMed rs1653153732
- D69E (p.Asp69Glu), ESP rs142709072, ExAC rs142709072, TOPMed rs142709072, gnomAD rs142709072
- D69N (p.Asp69Asn), rs1217700912, ClinGen CA341866834, ClinVar RCV003016956, gnomAD rs1217700912, REVEL 0.40, CADD 22.90, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- Q70E (p.Gln70Glu), Ensembl rs1653153296, REVEL 0.84, CADD 25.20
- Q70R (p.Gln70Arg), gnomAD rs1469630685
- T71A (p.Thr71Ala), TOPMed rs1571042738
- T71S (p.Thr71Ser), TOPMed rs1571042738, REVEL 0.19, CADD 18.10
- D72E (p.Asp72Glu), Ensembl rs1571042729, REVEL 0.22, CADD 7.23
- E74K (p.Glu74Lys), rs587688416, ClinGen CA1037934, ClinVar RCV001794522, 1000Genomes rs587688416, REVEL 0.87, CADD 26.60, Likely pathogenic, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- K75N (p.Lys75Asn), Ensembl rs774411362
- K75Q (p.Lys75Gln), Ensembl rs1571042703
- K75R (p.Lys75Arg), ExAC rs774598305, gnomAD rs774598305
- K75T (p.Lys75Thr), ExAC rs774598305, gnomAD rs774598305, REVEL 0.28, CADD 22.60
- Y76C (p.Tyr76Cys), gnomAD rs1413432644, REVEL 0.49, CADD 23.10, Uncertain significance, Inborn genetic diseases
- Y76F (p.Tyr76Phe), gnomAD rs1413432644, REVEL 0.30, CADD 8.25
- N78D (p.Asn78Asp), ExAC rs766584879, gnomAD rs766584879, REVEL 0.24, CADD 21.90
- V79M (p.Val79Met), ExAC rs763001714, TOPMed rs763001714, gnomAD rs763001714, REVEL 0.82, CADD 25.50
- A81T (p.Ala81Thr), rs151187711, ClinGen CA1037929, ClinVar RCV000490124, ClinVar RCV001065755, REVEL 0.38, CADD 22.40, Uncertain significance, Inborn genetic diseases; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; not
- G82E (p.Gly82Glu), rs1653149765, ClinGen CA341866618, NCI-TCGA Cosmic COSV6556, cosmic curated COSV65567, REVEL 0.90, CADD 25.50, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- K83N (p.Lys83Asn), gnomAD rs1420068119, REVEL 0.67, CADD 24.20
- K83R (p.Lys83Arg), gnomAD rs1462212320, REVEL 0.53, CADD 22.50
- Y84C (p.Tyr84Cys), TOPMed rs1162910493, gnomAD rs1162910493, REVEL 0.92, CADD 28.70
- T85P (p.Thr85Pro), ExAC rs776664327, gnomAD rs776664327, REVEL 0.97, CADD 27.00
- V86E (p.Val86Glu), gnomAD rs1187974723
- G87C (p.Gly87Cys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G87D (p.Gly87Asp), ExAC rs768463219, TOPMed rs768463219, gnomAD rs768463219, REVEL 0.94, CADD 25.80
- L88F (p.Leu88Phe), cosmic curated COSV65569, Ensembl rs2101273969
- L88S (p.Leu88Ser), gnomAD rs1270679177, REVEL 0.94, CADD 27.50
- G89A (p.Gly89Ala), 1000Genomes rs114033510, ExAC rs114033510, gnomAD rs114033510, REVEL 0.94, CADD 24.70
- T91I (p.Thr91Ile), 1000Genomes rs587697520, TOPMed rs587697520, gnomAD rs587697520, REVEL 0.50, CADD 21.90, Uncertain significance, Inborn genetic diseases
- T91S (p.Thr91Ser), 1000Genomes rs587697520, TOPMed rs587697520, gnomAD rs587697520, REVEL 0.18, CADD 15.80
- R92C (p.Arg92Cys), cosmic curated COSV10529, ExAC rs771955824, TOPMed rs771955824, gnomAD rs771955824, REVEL 0.31, CADD 22.90, Uncertain significance, not provided
- R92G (p.Arg92Gly), rs771955824, ClinGen CA1037919, ClinVar RCV002265482, ClinVar RCV003095999, REVEL 0.20, CADD 17.60, Uncertain significance, Inborn genetic diseases; not provided; 3-hydroxy-3-methylglutaryl-CoA synthase d
- R92H (p.Arg92His), rs144921290, ClinGen CA1037918, cosmic curated COSV65568, ClinVar RCV000262956, REVEL 0.29, CADD 3.01, Uncertain significance, not provided; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- R92S (p.Arg92Ser), ExAC rs771955824, TOPMed rs771955824, gnomAD rs771955824, Uncertain significance
- M93I (p.Met93Ile), rs1557994090, ClinGen CA341866452, NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- G94D (p.Gly94Asp), Ensembl rs2101273865, REVEL 0.92, CADD 25.00
- G94S (p.Gly94Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- F95L (p.Phe95Leu), Ensembl rs1653147167
- S97A (p.Ser97Ala), Ensembl rs1571042520
- S97L (p.Ser97Leu), rs1024035971, ClinGen CA30275209, ClinVar RCV004399673, TOPMed rs1024035971, REVEL 0.78, CADD 29.20, Uncertain significance, Inborn genetic diseases
- V98A (p.Val98Ala), Ensembl rs1571042499, REVEL 0.29, CADD 22.20
- V98F (p.Val98Phe), Ensembl rs1653146548, REVEL 0.55, CADD 25.40
- Q99H (p.Gln99His), 1000Genomes rs147746231, ESP rs147746231, ExAC rs147746231, TOPMed rs147746231
- Q99R (p.Gln99Arg), ExAC rs781647908, gnomAD rs781647908, REVEL 0.23, CADD 17.90
- E100K (p.Glu100Lys), rs1332784240, NCI-TCGA Cosmic COSV6556, cosmic curated COSV65567, Ensembl rs1332784240, REVEL 0.95, CADD 27.20, Variant assessed as somatic; moderate impact.
- E100V (p.Glu100Val), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65568, Variant assessed as somatic; moderate impact.
- D101G (p.Asp101Gly), ExAC rs751909473, TOPMed rs751909473, gnomAD rs751909473, REVEL 0.88, CADD 26.60
- D101V (p.Asp101Val), ExAC rs751909473, TOPMed rs751909473, gnomAD rs751909473, REVEL 0.89, CADD 26.20
- I102M (p.Ile102Met), TOPMed rs955697615, REVEL 0.76, CADD 25.20
- I102T (p.Ile102Thr), ExAC rs766672926, TOPMed rs766672926, gnomAD rs766672926, REVEL 0.85, CADD 26.80
- N103D (p.Asn103Asp), 1000Genomes rs2101273736
- S104Y (p.Ser104Tyr), ExAC rs763241833, gnomAD rs763241833
- L105V (p.Leu105Val), Ensembl rs1653144748
- C106* (p.Cys106Ter), cosmic curated COSV65568, gnomAD rs1426710599
- C106S (p.Cys106Ser), ExAC rs750575658, gnomAD rs750575658, REVEL 0.71, CADD 24.40
- T108K (p.Thr108Lys), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, NCI-TCGA Cosmic COSV6556, Variant assessed as somatic; moderate impact.
- T108M (p.Thr108Met), cosmic curated COSV65568, ExAC rs765384188, TOPMed rs765384188, gnomAD rs765384188, REVEL 0.88, CADD 27.60
- V109M (p.Val109Met), ExAC rs776751915, gnomAD rs776751915, REVEL 0.85, CADD 25.80
- V110M (p.Val110Met), rs1250760247, NCI-TCGA Cosmic COSV1010, cosmic curated COSV10102, TOPMed rs1250760247, REVEL 0.87, CADD 25.80, Variant assessed as somatic; moderate impact.
- Q111K (p.Gln111Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- R112Q (p.Arg112Gln), rs145633208, cosmic curated COSV10102, ESP rs145633208, ExAC rs145633208, REVEL 0.25, CADD 14.90, Uncertain significance, Inborn genetic diseases
- R112W (p.Arg112Trp), rs768707273, ClinGen CA1037908, ClinVar RCV002932473, UniProt VAR 083500, REVEL 0.55, CADD 24.60, Conflicting interpretations, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- M114K (p.Met114Lys), TOPMed rs1653142058, REVEL 0.95, CADD 24.50
- E115K (p.Glu115Lys), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65568, REVEL 0.75, CADD 23.80, Variant assessed as somatic; moderate impact.
- R116C (p.Arg116Cys), rs200607527, ClinGen CA312641, ClinVar RCV000185972, ClinVar RCV000697575, REVEL 0.73, CADD 26.50, Uncertain significance, not provided; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- R116H (p.Arg116His), rs147906427, ClinGen CA1037906, cosmic curated COSV65567, ClinVar RCV000700818, REVEL 0.77, CADD 24.20, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; not provided
- I117M (p.Ile117Met), TOPMed rs928663340, gnomAD rs928663340, REVEL 0.19, CADD 0.05
- I117R (p.Ile117Arg), Ensembl rs1571042378
- I117T (p.Ile117Thr), Ensembl rs1571042378
- I117V (p.Ile117Val), TOPMed rs1453735975, gnomAD rs1453735975, REVEL 0.16, CADD 14.60, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- Q118K (p.Gln118Lys), Ensembl rs1571042362
- Q118P (p.Gln118Pro), TOPMed rs1235493293, gnomAD rs1235493293, REVEL 0.24, CADD 19.20
- Q118R (p.Gln118Arg), TOPMed rs1235493293, gnomAD rs1235493293, REVEL 0.17, CADD 13.70
- P120S (p.Pro120Ser), ExAC rs758033248, TOPMed rs758033248, gnomAD rs758033248, Uncertain significance
- P120T (p.Pro120Thr), rs758033248, ClinGen CA1037904, ClinVar RCV000732849, ClinVar RCV001210292, REVEL 0.33, CADD 21.70, Uncertain significance, Inborn genetic diseases; not provided; 3-hydroxy-3-methylglutaryl-CoA synthase d
- W121C (p.Trp121Cys), ExAC rs770521945, gnomAD rs770521945, REVEL 0.53, CADD 23.40
- D122N (p.Asp122Asn), rs368014391, ClinGen CA312646, cosmic curated COSV65569, ClinVar RCV000185973, REVEL 0.31, CADD 17.80, Uncertain significance, not provided; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- S123A (p.Ser123Ala), TOPMed rs1300010645, gnomAD rs1300010645
- S123C (p.Ser123Cys), ExAC rs755489615, gnomAD rs755489615
- S123F (p.Ser123Phe), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65569, Variant assessed as somatic; moderate impact.
- S123T (p.Ser123Thr), cosmic curated COSV65567, TOPMed rs1300010645, gnomAD rs1300010645, REVEL 0.14, CADD 7.25
- S123Y (p.Ser123Tyr), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65567, Variant assessed as somatic; moderate impact.
- R126G (p.Arg126Gly), gnomAD rs1436348108
- R126S (p.Arg126Ser), cosmic curated COSV10606, gnomAD rs1393101212, REVEL 0.72, CADD 18.70
- E128K (p.Glu128Lys), rs2464281843, ClinGen CA341865684, ClinVar RCV003271801, Uncertain significance, Inborn genetic diseases
- V129I (p.Val129Ile), NCI-TCGA Cosmic COSV6556, cosmic curated COSV65567, REVEL 0.73, CADD 24.40, Variant assessed as somatic; moderate impact.
- G130D (p.Gly130Asp), cosmic curated COSV10102, ESP rs375313694, ExAC rs375313694, TOPMed rs375313694, REVEL 0.95, CADD 25.50
- E132D (p.Glu132Asp), ExAC rs753951770, REVEL 0.88, CADD 23.90
- I135T (p.Ile135Thr), cosmic curated COSV10102, gnomAD rs1350489274, REVEL 0.89, CADD 27.00
- D136G (p.Asp136Gly), rs2101273359, ClinGen CA341865396, ClinVar RCV001794528, Ensembl rs2101273359, Likely pathogenic, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- K137E (p.Lys137Glu), TOPMed rs1653138229, REVEL 0.91, CADD 28.10
- S138P (p.Ser138Pro), rs764209022, ClinGen CA1037893, ClinVar RCV001221290, ExAC rs764209022, REVEL 0.93, CADD 25.60, Uncertain significance, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
- S138V (p.Ser138Val), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K139* (p.Lys139Ter), gnomAD rs1232767876
- K139E (p.Lys139Glu), gnomAD rs1232767876
- V141A (p.Val141Ala), TOPMed rs1406920400, gnomAD rs1406920400, REVEL 0.81, CADD 26.50, Likely pathogenic
Public HMGCS2 analysis runs
- HMGCS2 analysis run — HMGCS2 (853 variants) — completed 2026-08-20