GeneBe

PAH

phenylalanine hydroxylase

Basic information

Region (hg38): 12:102836889-102958410

Links

ENSG00000171759 ∙ NCBI:5053 ∙ OMIM:612349 ∙ HGNC:8582 ∙ Uniprot:P00439 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • 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 (415 variants)
  • not provided (222 variants)
  • PAH-related disorder (38 variants)
  • Inborn genetic diseases (21 variants)
  • Hyperphenylalaninemia (18 variants)
  • See cases (7 variants)
  • 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (4 variants)
  • Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis (2 variants)
  • Pulmonary hypertension, primary, 1 (2 variants)
  • not specified (1 variants)
  • Mild hyperphenylalaninemia (1 variants)
  • Intellectual disability (1 variants)
  • Marfanoid habitus and intellectual disability (1 variants)
  • Pituitary hormone deficiency, combined, 2 (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.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
1
clinvar
17
clinvar
168
clinvar
8
clinvar
 194
missense
159
clinvar
308
clinvar
197
clinvar
1
clinvar
 665
nonsense
64
clinvar
14
clinvar
 78
start loss
4
clinvar
2
clinvar
 6
frameshift
114
clinvar
36
clinvar
 150
inframe indel
5
clinvar
7
clinvar
6
clinvar
 18
splice donor/acceptor (+/-2bp)
55
clinvar
21
clinvar
 76
splice region
14
18
33
41
1
 107
non coding
3
clinvar
4
clinvar
27
clinvar
118
clinvar
45
clinvar
 197
Total 404 393 247 287 53

Highest pathogenic variant AF is 0.000861

Variants in PAH

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

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
12-102838399-TTTAC-T Phenylketonuria Uncertain significance (Jun 14, 2016)306909
12-102838440-A-G Phenylketonuria Uncertain significance (Jan 13, 2018)306910
12-102838476-G-A Phenylketonuria Uncertain significance (Apr 28, 2017)880618
12-102838525-T-C Phenylketonuria Uncertain significance (Jan 13, 2018)880619
12-102838903-G-A Phenylketonuria Uncertain significance (Jan 12, 2018)880620
12-102838988-C-T Phenylketonuria Benign (Sep 22, 2018)306911
12-102839031-T-C Phenylketonuria • PAH-related disorder Uncertain significance (Dec 23, 2020)657680
12-102839096-C-T Phenylketonuria Uncertain significance (Jan 12, 2018)306912
12-102839133-T-C Phenylketonuria Uncertain significance (Apr 27, 2017)882030
12-102839156-C-A not specified • Phenylketonuria Uncertain significance (Sep 27, 2019)255733
12-102839172-GCTTTA-G Phenylketonuria Likely pathogenic (Jul 23, 2023)194161
12-102839178-C-CT Phenylketonuria Pathogenic/Likely pathogenic (Apr 18, 2024)102596
12-102839181-T-G Phenylketonuria • Inborn genetic diseases Likely benign (Apr 07, 2023)1124483
12-102839187-C-A Inborn genetic diseases Uncertain significance (Dec 08, 2023)3208023
12-102839190-G-A Phenylketonuria Likely benign (May 16, 2023)1146245
12-102839192-G-A Phenylketonuria • Inborn genetic diseases Uncertain significance (Feb 23, 2024)1912436
12-102839193-G-T Phenylketonuria Likely benign (May 07, 2019)1152040
12-102839194-G-T Phenylketonuria • PAH-related disorder Pathogenic (Feb 29, 2024)102595
12-102839195-C-T Phenylketonuria Pathogenic (Dec 24, 2024)857071
12-102839199-GC-G Phenylketonuria Likely pathogenic (Sep 08, 2022)2677439
12-102839200-C-A Phenylketonuria Uncertain significance (Aug 17, 2020)991615
12-102839202-A-C Phenylketonuria Likely benign (Aug 05, 2024)1108021
12-102839204-G-A Phenylketonuria Conflicting classifications of pathogenicity (Nov 07, 2024)551287
12-102839205-G-T Phenylketonuria Likely benign (Jan 19, 2022)1146470
12-102839216-C-A Phenylketonuria Likely pathogenic (May 15, 2020)932274

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