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GeneBe

PAH

phenylalanine hydroxylase

Basic information

Region (hg38): 12:102836888-102958410

Links

ENSG00000171759NCBI:5053OMIM:612349HGNC:8582Uniprot:P00439AlphaFoldGenCCjaxSfariGnomADPubmed

Phenotypes

GenCC

Source: genCC

  • phenylketonuria (Definitive), mode of inheritance: AR
  • phenylketonuria (Definitive), mode of inheritance: AR
  • phenylketonuria (Strong), mode of inheritance: AR
  • maternal phenylketonuria (Supportive), mode of inheritance: AR
  • mild phenylketonuria (Supportive), mode of inheritance: AR
  • classic phenylketonuria (Supportive), mode of inheritance: AR
  • mild hyperphenylalaninemia (Supportive), mode of inheritance: AR
  • tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria (Supportive), mode of inheritance: AR
  • phenylketonuria (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Phenylketonuria; Hyperphenylalaninemia, non-PKU mildARBiochemicalDietary measures, including avoidance of aspartame, as well as adjuvant medical therapy, can be effective in preventing severe sequelae, including in preconception/prenatal circumstancesBiochemical; Dermatologic; Neurologic13452670; 5391176; 3008810; 3945244; 2889860; 3308176; 3819940; 2279504; 1361103; 8353710; 7885543; 8828601; 8648535; 9066890; 10472530; 10685924; 10685922; 10636975; 10683054; 11328945; 12555935; 12408183; 11999982; 12501224; 14726806; 15303001; 17935162; 20123473; 20301677; 22669364; 22841515; 22854513; 23062575; 33485801

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PAH gene.

  • Phenylketonuria (1244 variants)
  • not provided (629 variants)
  • not specified (51 variants)
  • Inborn genetic diseases (34 variants)
  • Hyperphenylalaninemia (19 variants)
  • See cases (9 variants)
  • 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (6 variants)
  • Reduced phenylalanine hydroxylase level (4 variants)
  • Congenital central hypoventilation (3 variants)
  • Intellectual disability (3 variants)
  • Mild non-PKU hyperphenylalanemia (2 variants)
  • Haddad syndrome (1 variants)
  • - (1 variants)
  • Marfanoid habitus and intellectual disability (1 variants)
  • Dystonia 5 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PAH gene is commonly pathogenic or not.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous 1 2 6 148 9 166
missense 145 274 194 7 620
nonsense 56 17 1 74
start loss 0
frameshift 77 26 7 110
inframe indel 20 6 26
splice variant 64 36 35 31 1 167
non coding 8 8 27 58 52 153
Total 371 369 269 245 62

Highest pathogenic variant AF is 0.000861

Variants in PAH

This is a list of pathogenic ClinVar variants found in the PAH region.

Position Type Phenotype Significance ClinVar
12-102838399-TTTAC-T Phenylketonuria Uncertain significance (Jun 14, 2016)link
12-102838440-A-G Phenylketonuria Uncertain significance (Jan 13, 2018)link
12-102838476-G-A Phenylketonuria Uncertain significance (Apr 28, 2017)link
12-102838525-T-C Phenylketonuria Uncertain significance (Jan 13, 2018)link
12-102838903-G-A Phenylketonuria Uncertain significance (Jan 12, 2018)link
12-102838988-C-T Phenylketonuria Benign (Sep 22, 2018)link
12-102839031-T-C Phenylketonuria Uncertain significance (Dec 23, 2020)link
12-102839096-C-T Phenylketonuria Uncertain significance (Jan 12, 2018)link
12-102839133-T-C Phenylketonuria Uncertain significance (Apr 27, 2017)link
12-102839156-C-A not specified • Phenylketonuria Uncertain significance (Sep 27, 2019)link
12-102839172-GCTTTA-G Phenylketonuria Likely pathogenic (Jul 23, 2023)link
12-102839178-C-CT Phenylketonuria Pathogenic/Likely pathogenic (Feb 13, 2023)link
12-102839181-T-G Phenylketonuria • Inborn genetic diseases Likely benign (Aug 26, 2020)link
12-102839190-G-A Phenylketonuria Likely benign (Sep 22, 2021)link
12-102839192-G-A Phenylketonuria Uncertain significance (Sep 27, 2022)link
12-102839193-G-T Phenylketonuria Likely benign (May 07, 2019)link
12-102839194-G-T Phenylketonuria Pathogenic (Sep 12, 2022)link
12-102839195-C-T Phenylketonuria Pathogenic (Oct 15, 2022)link
12-102839200-C-A Phenylketonuria Uncertain significance (Aug 17, 2020)link
12-102839202-A-C Phenylketonuria Likely benign (Jun 29, 2022)link
12-102839204-G-A Phenylketonuria Conflicting interpretations of pathogenicity (Jul 23, 2022)link
12-102839205-G-T Phenylketonuria Likely benign (Jan 19, 2022)link
12-102839216-C-A Phenylketonuria Likely pathogenic (May 15, 2020)link
12-102839219-C-G Phenylketonuria Likely pathogenic (Dec 09, 2022)link
12-102839219-C-T Phenylketonuria Pathogenic (Jun 01, 2020)link

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
PAHprotein_codingprotein_codingENST00000553106 13121526
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
6.40e-230.00021312553402141257480.000851
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.6482712431.120.00001352956
Missense in Polyphen129105.41.22391291
Synonymous-0.8349989.01.110.00000446850
Loss of Function-0.5873228.61.120.00000165331

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0007850.000785
Ashkenazi Jewish0.00009920.0000992
East Asian0.0003260.000326
Finnish0.00009240.0000924
European (Non-Finnish)0.001500.00150
Middle Eastern0.0003260.000326
South Asian0.0003590.000359
Other0.0009780.000978

dbNSFP

Source: dbNSFP

Function
FUNCTION: Catalyzes the hydroxylation of L-phenylalanine to L- tyrosine. {ECO:0000269|PubMed:18460651, ECO:0000269|PubMed:18835579}.;
Disease
DISEASE: Phenylketonuria (PKU) [MIM:261600]: Autosomal recessive inborn error of phenylalanine metabolism, due to severe phenylalanine hydroxylase deficiency. It is characterized by blood concentrations of phenylalanine persistently above 1200 mumol (normal concentration 100 mumol) which usually causes mental retardation (unless low phenylalanine diet is introduced early in life). They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant 'mousy' odor. {ECO:0000269|PubMed:10200057, ECO:0000269|PubMed:10679941, ECO:0000269|PubMed:11180595, ECO:0000269|PubMed:11326337, ECO:0000269|PubMed:11385716, ECO:0000269|PubMed:11461196, ECO:0000269|PubMed:12501224, ECO:0000269|PubMed:1355066, ECO:0000269|PubMed:1363837, ECO:0000269|PubMed:1363838, ECO:0000269|PubMed:1671810, ECO:0000269|PubMed:1672290, ECO:0000269|PubMed:1672294, ECO:0000269|PubMed:1679030, ECO:0000269|PubMed:1709636, ECO:0000269|PubMed:18538294, ECO:0000269|PubMed:1975559, ECO:0000269|PubMed:2014802, ECO:0000269|PubMed:22513348, ECO:0000269|PubMed:22526846, ECO:0000269|PubMed:23792259, ECO:0000269|PubMed:2564729, ECO:0000269|PubMed:2615649, ECO:0000269|PubMed:2840952, ECO:0000269|PubMed:7833954, ECO:0000269|PubMed:8068076, ECO:0000269|PubMed:8406445, ECO:0000269|PubMed:8889583, ECO:0000269|PubMed:8889590, ECO:0000269|PubMed:9048935, ECO:0000269|PubMed:9101291, ECO:0000269|PubMed:9452061, ECO:0000269|PubMed:9452062, ECO:0000269|PubMed:9521426, ECO:0000269|PubMed:9600453, ECO:0000269|PubMed:9792407, ECO:0000269|PubMed:9792411, ECO:0000269|PubMed:9950317}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:261600]: Mild form of phenylalanine hydroxylase deficiency characterized by phenylalanine levels persistently below 600 mumol, which allows normal intellectual and behavioral development without treatment. Non-PKU HPA is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe one. {ECO:0000269|PubMed:1358789, ECO:0000269|PubMed:8088845, ECO:0000269|PubMed:8098245, ECO:0000269|PubMed:9521426, ECO:0000269|PubMed:9852673}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperphenylalaninemia (HPA) [MIM:261600]: Mildest form of phenylalanine hydroxylase deficiency. {ECO:0000269|PubMed:11385716, ECO:0000269|PubMed:11935335, ECO:0000269|PubMed:12501224, ECO:0000269|PubMed:1358789, ECO:0000269|PubMed:23792259, ECO:0000269|PubMed:8088845, ECO:0000269|PubMed:8098245, ECO:0000269|PubMed:9521426, ECO:0000269|PubMed:9852673}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway
Folate biosynthesis - Homo sapiens (human);Phenylalanine metabolism - Homo sapiens (human);Phenylalanine, tyrosine and tryptophan biosynthesis - Homo sapiens (human);Phenylalanine and Tyrosine Metabolism;Phenylketonuria;Tyrosinemia Type 3 (TYRO3);Tyrosinemia Type 2 (or Richner-Hanhart syndrome);Biogenic Amine Synthesis;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;phenylalanine degradation/tyrosine biosynthesis;Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism;Metabolism of amino acids and derivatives;Phenylalanine and tyrosine catabolism;Metabolism (Consensus)

Recessive Scores

pRec
0.857

Intolerance Scores

loftool
0.0132
rvis_EVS
-0.71
rvis_percentile_EVS
14.67

Haploinsufficiency Scores

pHI
0.130
hipred
Y
hipred_score
0.528
ghis
0.521

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.995

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Pah
Phenotype
homeostasis/metabolism phenotype; growth/size/body region phenotype; reproductive system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); pigmentation phenotype;

Zebrafish Information Network

Gene name
pah
Affected structure
musculoskeletal movement
Phenotype tag
abnormal
Phenotype quality
disrupted

Gene ontology

Biological process
L-phenylalanine catabolic process;tyrosine biosynthetic process;cellular amino acid biosynthetic process;neurotransmitter biosynthetic process;catecholamine biosynthetic process;oxidation-reduction process
Cellular component
cytosol
Molecular function
phenylalanine 4-monooxygenase activity;iron ion binding