PAH (Phenylalanine-4-hydroxylase) variants and mutations
PAH (also known as Phenylalanine-4-hydroxylase) is a human protein-coding gene encoding a phenylalanine-4-hydroxylase protein. It converts phenylalanine to tyrosine using tetrahydrobiopterin, preventing toxic phenylalanine accumulation. Biallelic loss-of-function variants cause phenylketonuria and related hyperphenylalaninemias, which can impair brain development without early treatment. This analysis covers 1,132 PAH variants and mutations. Of these, 93% have computational variant effect predictions. Disease context includes phenylketonuria, Hyperphenylalaninemia, and Maternal hyperphenylalaninemia. Example PAH variants include M1I, M1L, and M1R.
Variant analysis overview
- Gene: PAH
- Protein: Phenylalanine-4-hydroxylase
- UniProt accession: P00439
- Organism: Homo sapiens
- Variants analyzed: 1132
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,008 unspecified-consequence records; 1 stop lost; 66 synonymous variants; 32 missense variants; 3 stop-gained variants; 4 splice-region variants; 14 frameshift variants; 1 in-frame deletions; 3 substitution
- Prediction scores: 1,049 variants have prediction scores (93% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: phenylketonuria, Hyperphenylalaninemia, Maternal hyperphenylalaninemia, hereditary disease, 6-pyruvoyl-tetrahydropterin synthase deficiency, BH4-deficient hyperphenylalaninemia A, pulmonary hypertension, primary, 1, polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, mild hyperphenylalaninemia, malnutrition, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, Combined pituitary hormone deficiencies, genetic forms.
Protein structure and variant hotspots
- Protein features: 1 domains; 3 binding sites; 1 post-translational modification sites.
- Structural context: 150 variants have structural context.
- PTM context: 4 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 PAH variants
Examples include M1I, M1L, M1R, M1T, M1V, T3I, A4E, A4T. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1I (p.Met1Ile), rs62514893, ClinGen CA229532, ClinVar RCV000000653, ClinVar RCV000088911, MetaLR 0.97, MetaSVM 1.02, Pathogenic
- M1L (p.Met1Leu), rs62514891, ClinGen CA229482, ClinVar RCV000088869, ClinVar RCV000993611, MetaLR 0.96, MetaSVM 0.90, Pathogenic
- M1R (p.Met1Arg), rs62508575, ClinGen CA229509, ClinVar RCV000088893, ClinVar RCV000993612, MetaLR 0.97, MetaSVM 1.02, Pathogenic
- M1T (p.Met1Thr), rs62508575, ClinGen CA312807, ClinVar RCV000186076, ClinVar RCV000984289, MetaLR 0.97, MetaSVM 1.02, Pathogenic
- M1V (p.Met1Val), rs62514891, ClinGen CA114360, ClinVar RCV000000616, ClinVar RCV000000617, MetaLR 0.96, MetaSVM 0.90, Pathogenic
- T3I (p.Thr3Ile), TOPMed rs1451895979, REVEL 0.50, CADD 17.50
- A4E (p.Ala4Glu), NCI-TCGA TCGA novel, REVEL 0.60, CADD 2.24, Variant assessed as somatic; moderate impact.
- A4T (p.Ala4Thr), gnomAD rs1223872589
- A4V (p.Ala4Val), ExAC rs765022724, TOPMed rs765022724, gnomAD rs765022724, REVEL 0.60, CADD 3.06
- E7Q (p.Glu7Gln), ExAC rs753312947, REVEL 0.55, CADD 17.00
- N8D (p.Asn8Asp), rs763623193, ClinGen CA6749065, ClinVar RCV003099019, ExAC rs763623193, REVEL 0.52, CADD 7.14, Uncertain significance
- N8T (p.Asn8Thr), rs1878414153, ClinGen CA386303870, ClinVar RCV001109152, Ensembl rs1878414153, AlphaMissense 0.07, MetaLR 0.86, Uncertain significance
- P9Q (p.Pro9Gln), NCI-TCGA Cosmic COSV1001, SIFT 1.00, Variant assessed as somatic; moderate impact.
- G10C (p.Gly10Cys), NCI-TCGA Cosmic COSV6102, Variant assessed as somatic; moderate impact.
- G10S (p.Gly10Ser), NCI-TCGA Cosmic COSV6102, Variant assessed as somatic; moderate impact.
- G10V (p.Gly10Val), NCI-TCGA Cosmic COSV6101, SIFT 0.45, Variant assessed as somatic; moderate impact.
- L11* (p.Leu11Ter), rs1346707834, ClinGen CA386303850, ClinVar RCV000850222, gnomAD rs1346707834, CADD 33.00, Pathogenic
- L11F (p.Leu11Phe), NCI-TCGA Cosmic COSV1001, Variant assessed as somatic; moderate impact.
- L11S (p.Leu11Ser), gnomAD rs1346707834, REVEL 0.64, CADD 9.69, Pathogenic
- G12S (p.Gly12Ser), TOPMed rs1433712720, gnomAD rs1433712720, REVEL 0.60, CADD 9.54
- K14E (p.Lys14Glu), Ensembl rs1878412813, REVEL 0.61, CADD 17.50
- K14R (p.Lys14Arg), NCI-TCGA Cosmic COSV1001, SIFT 0.15, Variant assessed as somatic; moderate impact.
- L15H (p.Leu15His), rs1319374413, ClinGen CA386303822, ClinVar RCV001109151, TOPMed rs1319374413, AlphaMissense 0.07, MetaLR 0.86, Uncertain significance
- L15P (p.Leu15Pro), TOPMed rs1319374413, gnomAD rs1319374413, REVEL 0.56, AlphaMissense 0.07, Uncertain significance
- L15R (p.Leu15Arg), rs1319374413, ClinGen CA386303820, ClinVar RCV002834999, AlphaMissense 0.07, MetaLR 0.86, Uncertain significance
- L15V (p.Leu15Val), TOPMed rs1878412507
- S16F (p.Ser16Phe), NCI-TCGA Cosmic COSV1001, Ensembl rs1592991188, Uncertain significance, in PAH deficiency
- S16P (p.Ser16Pro), rs62642946, ClinGen CA229564, ClinVar RCV000088937, ClinVar RCV000993613, AlphaMissense 0.07, MetaLR 0.88, Uncertain significance, in PAH deficiency
- S16T (p.Ser16Thr), TOPMed rs62642946, Uncertain significance, in PAH deficiency
- S16Y (p.Ser16Tyr), rs1592991188, ClinGen CA16020719, ClinVar RCV000993598, Ensembl rs1592991188, AlphaMissense 0.09, MetaLR 0.88, Uncertain significance, in PAH deficiency
- D17* (p.Asp17Ter), rs1592991176, ClinGen CA16020720, ClinVar RCV000993599, Pathogenic
- D17E (p.Asp17Glu), ESP rs150366430, ExAC rs150366430, gnomAD rs150366430, REVEL 0.57, CADD 14.00
- G19R (p.Gly19Arg), ExAC rs771104344, TOPMed rs771104344, gnomAD rs771104344, REVEL 0.59, CADD 21.20, Uncertain significance
- Q20* (p.Gln20Ter), rs199475585, ClinGen CA229635, ClinVar RCV000088993, ClinVar RCV000169450, CADD 43.00, Pathogenic, in PAH deficiency
- Q20H (p.Gln20His), rs199475688, ClinGen CA229651, ClinVar RCV000089006, ClinVar RCV000993618, AlphaMissense 0.12, MetaLR 0.84, Uncertain significance, in PAH deficiency
- Q20L (p.Gln20Leu), rs199475662, ClinGen CA229641, ClinVar RCV000088998, ClinVar RCV000993617, REVEL 0.58, AlphaMissense 0.08, Uncertain significance, in PAH deficiency
- Q20P (p.Gln20Pro), rs199475662, ClinGen CA16020721, ClinVar RCV000993600, gnomAD rs199475662, AlphaMissense 0.08, MetaLR 0.83, Uncertain significance, in PAH deficiency
- Q20R (p.Gln20Arg), gnomAD rs199475662, REVEL 0.63, AlphaMissense 0.08, Uncertain significance, in PAH deficiency
- E21D (p.Glu21Asp), rs753466976, ClinGen CA6749050, ClinVar RCV001896984, ExAC rs753466976, REVEL 0.62, MetaLR 0.86, Uncertain significance
- T22A (p.Thr22Ala), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, Variant assessed as somatic; moderate impact.
- T22K (p.Thr22Lys), rs199565868, ClinGen CA6749049, ClinVar RCV000664768, ClinVar RCV002265840, REVEL 0.55, MetaLR 0.87, Uncertain significance
- T22S (p.Thr22Ser), TOPMed rs1878259731, gnomAD rs1878259731, REVEL 0.51, MetaLR 0.86
- S23I (p.Ser23Ile), NCI-TCGA Cosmic COSV6101, cosmic curated COSV61014, REVEL 0.62, MetaLR 0.89, Variant assessed as somatic; moderate impact.
- S23R (p.Ser23Arg), Ensembl rs913365395, REVEL 0.62, MetaLR 0.91
- Y24* (p.Tyr24Ter), rs2136728385, ClinGen CA386302770, ClinVar RCV003476585, Likely pathogenic
- Y24C (p.Tyr24Cys), rs539994406, ClinGen CA6749047, ClinVar RCV000529284, 1000Genomes rs539994406, REVEL 0.73, MetaLR 0.95, Uncertain significance
- Y24F (p.Tyr24Phe), 1000Genomes rs539994406, ExAC rs539994406, TOPMed rs539994406, gnomAD rs539994406, REVEL 0.67, MetaLR 0.93, Uncertain significance
- I25T (p.Ile25Thr), rs1355039694, ClinGen CA386302749, ClinVar RCV001980503, TOPMed rs1355039694, REVEL 0.59, MetaLR 0.85, Uncertain significance
- I25V (p.Ile25Val), TOPMed rs1878259032, MetaLR 0.89, MetaSVM 0.95
- E26K (p.Glu26Lys), TOPMed rs1878258606, REVEL 0.58, MetaLR 0.88
- D27E (p.Asp27Glu), Ensembl rs1878258443, Likely benign
- N30H (p.Asn30His), TOPMed rs936213897, REVEL 0.50, MetaLR 0.74
- Q31K (p.Gln31Lys), Ensembl rs1565873583, REVEL 0.61, MetaLR 0.75
- G33V (p.Gly33Val), rs2499542573, ClinGen CA386302590, ClinVar RCV002976127, Uncertain significance
- I35M (p.Ile35Met), rs768048739, ClinGen CA386302555, ClinVar RCV001279868, ExAC rs768048739, AlphaMissense 0.12, MetaLR 0.79, Uncertain significance
- S36L (p.Ser36Leu), ExAC rs760011862, gnomAD rs760011862, REVEL 0.77, MetaLR 0.97
- L37P (p.Leu37Pro), rs869312996, ClinGen CA357242, NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, REVEL 0.98, MetaLR 0.99, Likely pathogenic
- I38M (p.Ile38Met), Ensembl rs1878257168, MetaLR 0.88, MetaSVM 0.88
- F39L (p.Phe39Leu), rs62642926, ClinGen CA251537, ClinVar RCV000000636, ClinVar RCV000078504, REVEL 0.75, MetaLR 0.95, Pathogenic, in PAH deficiency
- S40L (p.Ser40Leu), rs62642938, ClinGen CA229393, NCI-TCGA Cosmic COSV6101, cosmic curated COSV61016, AlphaMissense 0.25, MetaLR 0.98, Pathogenic, in PAH deficiency
- L41F (p.Leu41Phe), rs62642928, ClinGen CA229401, ClinVar RCV000088803, ClinVar RCV000697659, AlphaMissense 0.65, MetaLR 0.98, Pathogenic, in PAH deficiency
- L41P (p.Leu41Pro), rs62642916, ClinGen CA229408, ClinVar RCV000088809, ClinVar RCV001093507, AlphaMissense 0.93, MetaLR 0.97, Likely pathogenic, in PAH deficiency
- K42I (p.Lys42Ile), rs62635346, ClinGen CA229419, cosmic curated COSV61017, ClinVar RCV000088819, AlphaMissense 0.08, MetaLR 0.90, Pathogenic, in PAH deficiency
- K42R (p.Lys42Arg), rs62635346, ClinGen CA6749044, ClinVar RCV002019669, ExAC rs62635346, REVEL 0.60, AlphaMissense 0.08, Likely pathogenic, in PAH deficiency
- E43* (p.Glu43Ter), rs1555209575, ClinGen CA16020729, ClinVar RCV000673220, Ensembl rs1555209575, Pathogenic
- E43G (p.Glu43Gly), gnomAD rs1878255644, REVEL 0.82, MetaLR 0.95
- E44* (p.Glu44Ter), rs2499542475, ClinVar RCV004574421, Likely pathogenic
- E44K (p.Glu44Lys), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, Variant assessed as somatic; moderate impact.
- V45A (p.Val45Ala), rs1592988883, ClinGen CA16020730, ClinVar RCV000993626, UniProt VAR 067994, REVEL 0.70, MetaLR 0.91, Uncertain significance, in PAH deficiency
- V45D (p.Val45Asp), NCI-TCGA Cosmic COSV6101, cosmic curated COSV61016, MetaLR 0.96, MetaSVM 1.08, Uncertain significance, in PAH deficiency
- V45F (p.Val45Phe), rs1878255139, ClinGen CA386302394, ClinVar RCV001247948, Ensembl rs1878255139, REVEL 0.88, MetaLR 0.97, Pathogenic, in PAH deficiency
- G46R (p.Gly46Arg), rs74603784, ClinGen CA16020731, ClinVar RCV000758110, ExAC rs74603784, REVEL 0.91, MetaLR 1.00, Pathogenic, in PAH deficiency
- G46S (p.Gly46Ser), rs74603784, ClinGen CA229439, ClinVar RCV000000661, ClinVar RCV000088836, REVEL 0.90, MetaLR 1.00, Pathogenic, in PAH deficiency
- G46V (p.Gly46Val), Ensembl rs2136728171, MetaLR 1.00, MetaSVM 0.93
- A47E (p.Ala47Glu), rs118203925, ClinGen CA229441, ClinVar RCV000088838, TOPMed rs118203925, AlphaMissense 0.22, MetaLR 0.94, Pathogenic, in PAH deficiency
- A47S (p.Ala47Ser), TOPMed rs1206656229, gnomAD rs1206656229, REVEL 0.58, MetaLR 0.94
- A47V (p.Ala47Val), rs118203925, ClinGen CA114370, ClinVar RCV000000662, ClinVar RCV000088839, REVEL 0.80, AlphaMissense 0.22, Pathogenic, in PAH deficiency
- L48F (p.Leu48Phe), cosmic curated COSV61016, gnomAD rs1878253594, REVEL 0.81, MetaLR 0.99
- L48S (p.Leu48Ser), rs5030841, ClinGen CA251539, ClinVar RCV000000639, ClinVar RCV000078511, REVEL 0.97, MetaLR 0.99, Pathogenic, in PAH deficiency
- A49D (p.Ala49Asp), rs1878253465, ClinGen CA386302329, ClinVar RCV001093427, Ensembl rs1878253465, REVEL 0.86, AlphaMissense 0.35, Uncertain significance
- A49V (p.Ala49Val), rs1878253465, ClinGen CA386302327, ClinVar RCV001995430, Ensembl rs1878253465, AlphaMissense 0.35, MetaLR 0.92, Uncertain significance
- K50* (p.Lys50Ter), rs776829633, ClinGen CA386302322, ClinVar RCV002306556, AlphaMissense 0.24, MetaLR 0.91, Likely pathogenic
- K50E (p.Lys50Glu), rs776829633, ClinGen CA6749041, ClinVar RCV002303977, ExAC rs776829633, REVEL 0.62, AlphaMissense 0.24, Uncertain significance
- V51I (p.Val51Ile), ExAC rs772159852, gnomAD rs772159852, REVEL 0.53, MetaLR 0.90
- L52S (p.Leu52Ser), rs199475630, ClinGen CA229443, ClinVar RCV000088840, ClinVar RCV001389300, REVEL 0.97, MetaLR 0.99, Pathogenic
- R53C (p.Arg53Cys), rs199475619, ClinGen CA229445, NCI-TCGA Cosmic COSV6101, cosmic curated COSV61017, REVEL 0.77, AlphaMissense 0.51, Likely pathogenic, in PAH deficiency
- R53G (p.Arg53Gly), rs199475619, ClinVar RCV004586231, AlphaMissense 0.51, MetaLR 0.87, Uncertain significance, in PAH deficiency
- R53H (p.Arg53His), rs118092776, ClinGen CA229447, cosmic curated COSV61020, ClinVar RCV000088842, REVEL 0.79, MetaLR 0.90, Benign, in PAH deficiency
- R53S (p.Arg53Ser), rs199475619, ClinGen CA6749039, ClinVar RCV001990771, ExAC rs199475619, REVEL 0.62, AlphaMissense 0.51, Likely pathogenic, in PAH deficiency
- L54F (p.Leu54Phe), ESP rs143358918, ExAC rs143358918, TOPMed rs143358918, gnomAD rs143358918, REVEL 0.71, MetaLR 0.93
- L54S (p.Leu54Ser), rs199475677, ClinGen CA229448, ClinVar RCV000088843, ClinVar RCV000669099, REVEL 0.88, MetaLR 0.97, Likely pathogenic
- F55L (p.Phe55Leu), rs199475598, ClinGen CA273114, ClinVar RCV000078512, ClinVar RCV000150092, REVEL 0.85, MetaLR 0.96, Pathogenic, in PAH deficiency
- F55S (p.Phe55Ser), rs281865438, ClinGen CA267639, ClinVar RCV000106347, Ensembl rs281865438, REVEL 0.96, MetaLR 0.99, Likely pathogenic, in PAH deficiency
- E56D (p.Glu56Asp), rs199475567, ClinGen CA229459, ClinVar RCV000088852, ClinVar RCV001543635, AlphaMissense 0.75, MetaLR 0.90, Pathogenic, in PAH deficiency
- E57* (p.Glu57Ter), rs140945592, ClinGen CA267642, ClinVar RCV000106349, ESP rs140945592, AlphaMissense 0.12, MetaLR 0.91, Pathogenic
- E57K (p.Glu57Lys), rs140945592, ClinGen CA220578, cosmic curated COSV61017, ClinVar RCV000078515, REVEL 0.51, AlphaMissense 0.12, Pathogenic
- D59G (p.Asp59Gly), rs199475672, ClinGen CA229468, ClinVar RCV000088858, ClinVar RCV000758114, AlphaMissense 0.22, MetaLR 0.93, Uncertain significance
- D59V (p.Asp59Val), rs199475672, ClinGen CA16020736, NCI-TCGA Cosmic COSV6102, cosmic curated COSV61020, REVEL 0.75, AlphaMissense 0.22, Uncertain significance
- D59Y (p.Asp59Tyr), rs199475635, ClinGen CA229466, ClinVar RCV000088857, ClinVar RCV002259585, AlphaMissense 0.17, MetaLR 0.95, Uncertain significance
- V60A (p.Val60Ala), gnomAD rs1398246301, REVEL 0.69, MetaLR 0.96
- V60I (p.Val60Ile), Ensembl rs2136702198
- N61D (p.Asn61Asp), rs199475651, ClinGen CA229470, ClinVar RCV000088859, ClinVar RCV001389299, AlphaMissense 0.37, MetaLR 0.97, Pathogenic, in PAH deficiency
- N61I (p.Asn61Ile), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, Variant assessed as somatic; moderate impact., in PAH deficiency
- N61K (p.Asn61Lys), rs199475634, ClinGen CA229471, ClinVar RCV000088860, ClinVar RCV001199974, REVEL 0.81, MetaLR 0.99, Pathogenic, in PAH deficiency
- N61S (p.Asn61Ser), rs2136702181, ClinGen CA386304246, ClinVar RCV002029638, Ensembl rs2136702181, AlphaMissense 0.08, MetaLR 0.95, Likely pathogenic, in PAH deficiency
- L62P (p.Leu62Pro), rs1877437661, ClinGen CA16020739, ClinVar RCV001093519, ClinVar RCV005236597, AlphaMissense 0.99, MetaLR 0.99, Pathogenic, in PAH deficiency
- L62V (p.Leu62Val), rs1565866640, ClinGen CA16020738, ClinVar RCV000758095, Ensembl rs1565866640, AlphaMissense 0.25, MetaLR 0.93, Uncertain significance, in PAH deficiency
- T63A (p.Thr63Ala), gnomAD rs199475568, REVEL 0.59, MetaLR 0.95, Likely pathogenic
- T63I (p.Thr63Ile), Ensembl rs989506392, REVEL 0.66, MetaLR 0.97
- T63P (p.Thr63Pro), rs199475568, ClinGen CA229473, ClinVar RCV000088861, ClinVar RCV000758120, REVEL 0.77, MetaLR 0.98, Likely pathogenic
- H64N (p.His64Asn), rs199475569, ClinGen CA229475, ClinVar RCV000088862, ClinVar RCV000758122, REVEL 0.66, MetaLR 0.96, Uncertain significance
- I65L (p.Ile65Leu), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, Variant assessed as somatic; moderate impact., in PAH deficiency
- I65N (p.Ile65Asn), rs75193786, ClinGen CA229479, ClinVar RCV000088865, ClinVar RCV000758100, AlphaMissense 1.00, MetaLR 0.99, Pathogenic, in PAH deficiency
- I65S (p.Ile65Ser), rs75193786, ClinGen CA229480, ClinVar RCV000088866, ClinVar RCV005606647, AlphaMissense 1.00, MetaLR 0.99, Pathogenic, in PAH deficiency
- I65T (p.Ile65Thr), rs75193786, ClinGen CA251544, ClinVar RCV000000668, ClinVar RCV000078516, REVEL 0.98, AlphaMissense 1.00, Pathogenic, in PAH deficiency
- I65V (p.Ile65Val), rs199475643, ClinGen CA229478, ClinVar RCV000088864, ClinVar RCV000803656, REVEL 0.80, MetaLR 0.98, Pathogenic, in PAH deficiency
- E66* (p.Glu66Ter), rs281865454, ClinGen CA267645, NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, AlphaMissense 0.95, MetaLR 0.98, Pathogenic
- E66K (p.Glu66Lys), rs281865454, ClinGen CA16020744, ClinVar RCV002260502, Ensembl rs281865454, AlphaMissense 0.95, MetaLR 0.98, Pathogenic
- S67A (p.Ser67Ala), rs5030842, ClinGen CA386304221, ClinVar RCV003328729, AlphaMissense 1.00, MetaLR 0.99, Pathogenic, in PAH deficiency
- S67C (p.Ser67Cys), rs2136702072, ClinGen CA386304219, NCI-TCGA Cosmic COSV6101, cosmic curated COSV61017, AlphaMissense 0.76, MetaLR 0.99, Uncertain significance, in PAH deficiency
- S67P (p.Ser67Pro), rs5030842, ClinGen CA229481, ClinVar RCV000088867, ClinVar RCV001260324, REVEL 0.95, AlphaMissense 1.00, Pathogenic, in PAH deficiency
- S67Y (p.Ser67Tyr), rs2136702072, ClinGen CA386304220, ClinVar RCV003034020, REVEL 0.92, AlphaMissense 0.76, Likely pathogenic, in PAH deficiency
- R68G (p.Arg68Gly), rs199475639, ClinGen CA229484, ClinVar RCV000088870, ClinVar RCV001543636, AlphaMissense 0.98, MetaLR 0.99, Pathogenic, in PAH deficiency
- R68S (p.Arg68Ser), rs76394784, ClinGen CA273113, ClinVar RCV000078517, ClinVar RCV000150091, REVEL 0.90, MetaLR 0.98, Pathogenic, in PAH deficiency
- P69L (p.Pro69Leu), rs1877434841, ClinGen CA386304208, ClinVar RCV003496249, AlphaMissense 0.44, MetaLR 0.99, Uncertain significance
- P69R (p.Pro69Arg), Ensembl rs1877434841
- P69S (p.Pro69Ser), rs199475678, ClinGen CA229486, NCI-TCGA Cosmic COSV6101, cosmic curated COSV61015, AlphaMissense 0.48, MetaLR 0.97, Likely pathogenic
- S70F (p.Ser70Phe), rs1877434368, ClinGen CA16020747, ClinVar RCV001269066, Ensembl rs1877434368, AlphaMissense 0.85, MetaLR 0.98, Likely pathogenic
- S70P (p.Ser70Pro), rs63048261, ClinGen CA229488, ClinVar RCV000088874, ClinVar RCV002259586, AlphaMissense 0.87, MetaLR 0.98, Likely pathogenic
- R71C (p.Arg71Cys), rs866012140, ClinGen CA16020748, cosmic curated COSV61017, ClinVar RCV003058394, REVEL 0.73, MetaLR 0.98, Likely pathogenic
- R71H (p.Arg71His), rs62508695, ClinGen CA286499, NCI-TCGA Cosmic COSV6101, cosmic curated COSV61019, REVEL 0.75, AlphaMissense 0.09, Pathogenic
- R71P (p.Arg71Pro), rs62508695, ClinGen CA16020749, ClinVar RCV001994069, TOPMed rs62508695, AlphaMissense 0.09, MetaLR 0.95, Pathogenic
- L72V (p.Leu72Val), rs760782775, ClinGen CA6748997, ClinVar RCV002627181, ExAC rs760782775, REVEL 0.55, MetaLR 0.86, Uncertain significance
- K73E (p.Lys73Glu), Ensembl rs905692464
- K73R (p.Lys73Arg), Ensembl rs1877433097, MetaLR 0.89, MetaSVM 0.64
- K74N (p.Lys74Asn), NCI-TCGA Cosmic COSV6101, cosmic curated COSV61013, MetaLR 0.92, MetaSVM 1.00, Variant assessed as somatic; moderate impact.
- D75G (p.Asp75Gly), rs1565866547, ClinGen CA16020750, ClinVar RCV000758118, Ensembl rs1565866547, AlphaMissense 0.06, MetaLR 0.76, Likely pathogenic
- D75H (p.Asp75His), rs767453024, ClinGen CA386304179, ClinVar RCV001269068, ClinVar RCV004526825, AlphaMissense 0.07, MetaLR 0.87, Likely pathogenic
- D75N (p.Asp75Asn), rs767453024, ClinGen CA6748995, cosmic curated COSV10645, ClinVar RCV000805522, REVEL 0.41, AlphaMissense 0.07, Likely pathogenic
- D75V (p.Asp75Val), rs1565866547, ClinGen CA16020751, ClinVar RCV000758113, Ensembl rs1565866547, AlphaMissense 0.06, MetaLR 0.76, Likely pathogenic
- E76* (p.Glu76Ter), rs762949770, ClinGen CA16020752, ClinVar RCV000590560, ExAC rs762949770, CADD 36.00, Pathogenic, in PAH deficiency
- E76A (p.Glu76Ala), rs62507347, ClinGen CA229492, ClinVar RCV000088877, ClinVar RCV001389298, AlphaMissense 0.20, MetaLR 0.93, Pathogenic, in PAH deficiency
- E76G (p.Glu76Gly), rs62507347, ClinGen CA114373, ClinVar RCV000000671, ClinVar RCV000088878, REVEL 0.64, AlphaMissense 0.20, Pathogenic, in PAH deficiency
- E76Q (p.Glu76Gln), ExAC rs762949770, gnomAD rs762949770, REVEL 0.62, MetaLR 0.84, Pathogenic, in PAH deficiency
- Y77* (p.Tyr77Ter), rs62507332, ClinGen CA229493, ClinVar RCV000088879, ClinVar RCV003479001, Pathogenic
- Y77H (p.Tyr77His), rs1877431851, ClinGen CA386304171, ClinVar RCV003316903, TOPMed rs1877431851, AlphaMissense 0.77, MetaLR 0.98, Uncertain significance
- E78D (p.Glu78Asp), rs2136701879, ClinGen CA386304160, NCI-TCGA Cosmic COSV6101, cosmic curated COSV61013, AlphaMissense 0.60, MetaLR 0.89, Uncertain significance
- E78K (p.Glu78Lys), rs62507326, ClinGen CA229495, cosmic curated COSV61014, ClinVar RCV000088880, REVEL 0.83, AlphaMissense 0.89, Likely pathogenic
- E78Q (p.Glu78Gln), rs62507326, ClinGen CA16020754, ClinVar RCV001093502, Ensembl rs62507326, AlphaMissense 0.89, MetaLR 0.98, Likely pathogenic
- E78V (p.Glu78Val), rs1877431301, ClinGen CA16020755, ClinVar RCV001093503, Ensembl rs1877431301, REVEL 0.82, MetaLR 0.95, Uncertain significance
- F79C (p.Phe79Cys), gnomAD rs1877431161, REVEL 0.83, MetaLR 0.98
- T81N (p.Thr81Asn), rs796064502, ClinGen CA275937, ClinVar RCV000190376, Ensembl rs796064502, REVEL 0.86, MetaLR 0.88, Likely pathogenic
- T81P (p.Thr81Pro), rs62509017, ClinGen CA229497, ClinVar RCV000088881, ClinVar RCV001192889, REVEL 0.74, MetaLR 0.91, Pathogenic
- H82N (p.His82Asn), ExAC rs769705809, gnomAD rs769705809, REVEL 0.50, MetaLR 0.51
- H82R (p.His82Arg), gnomAD rs1349393789, MetaLR 0.66, MetaSVM -0.05
- D84N (p.Asp84Asn), rs62514902, ClinGen CA386304125, ClinVar RCV003599346, REVEL 0.53, MetaLR 0.95, Likely pathogenic, in PAH deficiency
- D84Y (p.Asp84Tyr), rs62514902, ClinGen CA229500, ClinVar RCV000088883, ClinVar RCV000761308, REVEL 0.82, MetaLR 0.98, Pathogenic, in PAH deficiency
- K85* (p.Lys85Ter), rs1877430029, ClinGen CA16020757, ClinVar RCV001199993, Ensembl rs1877430029, Pathogenic
- R86C (p.Arg86Cys), ExAC rs768320548, TOPMed rs768320548, gnomAD rs768320548, REVEL 0.61, MetaLR 0.80
- R86H (p.Arg86His), rs746603180, ClinGen CA6748989, cosmic curated COSV61013, ClinVar RCV002771129, REVEL 0.59, MetaLR 0.64, Uncertain significance
- R86L (p.Arg86Leu), ExAC rs746603180, TOPMed rs746603180, gnomAD rs746603180, MetaLR 0.81, MetaSVM 0.14, Uncertain significance
- S87N (p.Ser87Asn), ESP rs368152528, TOPMed rs368152528, gnomAD rs368152528, REVEL 0.51, MetaLR 0.86
- S87R (p.Ser87Arg), rs62516151, ClinGen CA114359, ClinVar RCV000000613, ClinVar RCV000088884, REVEL 0.63, MetaLR 0.87, Pathogenic, in PAH deficiency
- P89S (p.Pro89Ser), rs62507270, ClinGen CA229501, cosmic curated COSV10512, ClinVar RCV000088886, REVEL 0.47, MetaLR 0.84, Pathogenic
- P89T (p.Pro89Thr), rs62507270, ClinGen CA242509800, cosmic curated COSV10018, ClinVar RCV003598634, REVEL 0.46, MetaLR 0.88, Pathogenic
- A90S (p.Ala90Ser), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10018, MetaLR 0.89, MetaSVM 0.65, Variant assessed as somatic; moderate impact.
- T92I (p.Thr92Ile), rs62514903, ClinGen CA229504, ClinVar RCV000088888, ClinVar RCV001854512, REVEL 0.60, MetaLR 0.83, Pathogenic, in PAH deficiency
- N93D (p.Asn93Asp), TOPMed rs1257495145, gnomAD rs1257495145, REVEL 0.57, MetaLR 0.80
- I94S (p.Ile94Ser), rs62508677, ClinGen CA229505, ClinVar RCV000088889, ClinVar RCV000673537, REVEL 0.75, MetaLR 0.94, Pathogenic, in PAH deficiency
- I94T (p.Ile94Thr), NCI-TCGA Cosmic COSV6102, cosmic curated COSV61020, MetaLR 0.92, MetaSVM 0.96, Variant assessed as somatic; moderate impact., in PAH deficiency
- I94V (p.Ile94Val), rs528078207, ClinGen CA6748988, ClinVar RCV001114785, ClinVar RCV003226435, REVEL 0.55, MetaLR 0.84, Uncertain significance, in PAH deficiency
- I95F (p.Ile95Phe), rs62508682, ClinGen CA229507, ClinVar RCV000088890, ClinVar RCV000763292, REVEL 0.66, MetaLR 0.94, Likely pathogenic
- I95L (p.Ile95Leu), ExAC rs62508682, TOPMed rs62508682, gnomAD rs62508682, MetaLR 0.90, MetaSVM 0.84, Likely pathogenic
- I95T (p.Ile95Thr), rs281865432, ClinGen CA267649, ClinVar RCV000106353, ClinVar RCV003390792, REVEL 0.72, MetaLR 0.97, Uncertain significance
- K96M (p.Lys96Met), Ensembl rs2136701686, MetaLR 0.91, MetaSVM 0.75
- I97L (p.Ile97Leu), rs142516271, ClinGen CA6748987, ClinVar RCV000430873, ClinVar RCV000664524, REVEL 0.51, MetaLR 0.76, Uncertain significance
- I97V (p.Ile97Val), 1000Genomes rs142516271, ESP rs142516271, ExAC rs142516271, TOPMed rs142516271, MetaLR 0.88, MetaSVM 0.48, Uncertain significance
- L98S (p.Leu98Ser), rs62517167, ClinGen CA114368, ClinVar RCV000000659, ClinVar RCV000088892, REVEL 0.85, MetaLR 0.99, Pathogenic, in PAH deficiency
- L98V (p.Leu98Val), rs1592978725, ClinGen CA16020761, ClinVar RCV000993634, Ensembl rs1592978725, AlphaMissense 0.27, MetaLR 0.96, Likely pathogenic, in PAH deficiency
- R99G (p.Arg99Gly), rs2136701651, ClinGen CA386304039, ClinVar RCV001975307, Ensembl rs2136701651, AlphaMissense 0.34, MetaLR 0.94, Uncertain significance
Public PAH analysis runs
- PAH analysis run — PAH (1,132 variants) — completed 2026-08-18