PAH
phenylalanine hydroxylase
Basic information
Region (hg38): 12:102836888-102958410
Links
Phenotypes
GenCC
Source:
- 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:
| 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
- 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) | ||
| 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 | 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 (Feb 13, 2023) | ||
| 12-102839181-T-G | Phenylketonuria • Inborn genetic diseases | Likely benign (Aug 26, 2020) | ||
| 12-102839190-G-A | Phenylketonuria | Likely benign (Sep 22, 2021) | ||
| 12-102839192-G-A | Phenylketonuria | Uncertain significance (Sep 27, 2022) | ||
| 12-102839193-G-T | Phenylketonuria | Likely benign (May 07, 2019) | ||
| 12-102839194-G-T | Phenylketonuria | Pathogenic (Sep 12, 2022) | ||
| 12-102839195-C-T | Phenylketonuria | Pathogenic (Oct 15, 2022) | ||
| 12-102839200-C-A | Phenylketonuria | Uncertain significance (Aug 17, 2020) | ||
| 12-102839202-A-C | Phenylketonuria | Likely benign (Jun 29, 2022) | ||
| 12-102839204-G-A | Phenylketonuria | Conflicting interpretations of pathogenicity (Jul 23, 2022) | ||
| 12-102839205-G-T | Phenylketonuria | Likely benign (Jan 19, 2022) | ||
| 12-102839216-C-A | Phenylketonuria | Likely pathogenic (May 15, 2020) | ||
| 12-102839219-C-G | Phenylketonuria | Likely pathogenic (Dec 09, 2022) | ||
| 12-102839219-C-T | Phenylketonuria | Pathogenic (Jun 01, 2020) |
GnomAD
Source:
| 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:
- 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