PAH

phenylalanine hydroxylase

Basic information

Region (hg38): 12:102836888-102958410

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 (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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Phenylketonuria; Hyperphenylalaninemia, non-PKU mild	AR	Biochemical	Dietary measures, including avoidance of aspartame, as well as adjuvant medical therapy, can be effective in preventing severe sequelae, including in preconception/prenatal circumstances	Biochemical; Dermatologic; Neurologic	13452670; 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 (1310 variants)
• not provided (612 variants)
• not specified (52 variants)
• Inborn genetic diseases (41 variants)
• PAH-related condition (21 variants)
• Hyperphenylalaninemia (18 variants)
• See cases (9 variants)
• 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (6 variants)
• Reduced phenylalanine hydroxylase level (4 variants)
• Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis (2 variants)
• Intellectual disability (2 variants)
• Mild non-PKU hyperphenylalanemia (2 variants)
• - (1 variants)
• Marfanoid habitus and intellectual disability (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	17	144	8	170
missense	156	275	197	2		630
nonsense	60	13				73
start loss	4	2				6
frameshift	111	32				143
inframe indel	5	7	6			18
splice donor/acceptor (+/-2bp)	57	21				78
splice region	11	17	34	34	1	97
non coding	3	4	26	68	44	145
Total	396	355	246	214	52

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)
12-102838440-A-G		Phenylketonuria	Uncertain significance (Jan 13, 2018)
12-102838476-G-A		Phenylketonuria	Uncertain significance (Apr 28, 2017)
12-102838525-T-C		Phenylketonuria	Uncertain significance (Jan 13, 2018)
12-102838903-G-A		Phenylketonuria	Uncertain significance (Jan 12, 2018)
12-102838988-C-T		Phenylketonuria	Benign (Sep 22, 2018)
12-102839031-T-C		Phenylketonuria • PAH-related condition	Uncertain significance (Dec 23, 2020)
12-102839096-C-T		Phenylketonuria	Uncertain significance (Jan 12, 2018)
12-102839133-T-C		Phenylketonuria	Uncertain significance (Apr 27, 2017)
12-102839156-C-A		not specified • Phenylketonuria	Uncertain significance (Sep 27, 2019)
12-102839172-GCTTTA-G		Phenylketonuria	Likely pathogenic (Jul 23, 2023)
12-102839178-C-CT		Phenylketonuria	Pathogenic/Likely pathogenic (Jul 03, 2023)
12-102839181-T-G		Phenylketonuria • Inborn genetic diseases	Likely benign (Apr 07, 2023)
12-102839187-C-A		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)
12-102839190-G-A		Phenylketonuria	Likely benign (May 16, 2023)
12-102839192-G-A		Phenylketonuria • Inborn genetic diseases	Uncertain significance (Jan 22, 2024)
12-102839193-G-T		Phenylketonuria	Likely benign (May 07, 2019)
12-102839194-G-T		Phenylketonuria • PAH-related condition	Pathogenic (Dec 01, 2023)
12-102839195-C-T		Phenylketonuria	Pathogenic (Jan 16, 2023)
12-102839199-GC-G		Phenylketonuria	Likely pathogenic (Sep 08, 2022)
12-102839200-C-A		Phenylketonuria	Uncertain significance (Aug 17, 2020)
12-102839202-A-C		Phenylketonuria	Likely benign (Jan 30, 2024)
12-102839204-G-A		Phenylketonuria	Conflicting classifications of pathogenicity (Mar 24, 2023)
12-102839205-G-T		Phenylketonuria	Likely benign (Jan 19, 2022)
12-102839216-C-A		Phenylketonuria	Likely pathogenic (May 15, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PAH	protein_coding	protein_coding	ENST00000553106	13	121526

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.40e-23	0.000213	125534	0	214	125748	0.000851

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.648	271	243	1.12	0.0000135	2956
Missense in Polyphen		129	105.4	1.2239		1291
Synonymous	-0.834	99	89.0	1.11	0.00000446	850
Loss of Function	-0.587	32	28.6	1.12	0.00000165	331

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000785	0.000785
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000326	0.000326
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.00150	0.00150
Middle Eastern	0.000326	0.000326
South Asian	0.000359	0.000359
Other	0.000978	0.000978

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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