PAH

Chr 12AR

phenylalanine hydroxylase

Also known as: PH, PKU, PKU1

NCBI Gene: 5053 ENSG00000171759 UniProt: P00439 OMIM: 612349

The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine as the rate-limiting step in phenylalanine catabolism. Mutations cause autosomal recessive phenylketonuria and milder hyperphenylalaninemia through deficiency of enzyme activity. Loss of function mutations result in accumulation of phenylalanine and its metabolites, leading to intellectual disability if untreated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.502 OMIM phenotypes

VCEP Guidelines: PhenylketonuriaReleased

ClinGen Panel

Clinical Summary— PAH

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Gene-Disease Validity (ClinGen)

phenylketonuria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

913 unique Pathogenic / Likely Pathogenic· 352 VUS of 1757 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PAH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.50LOEUF

pLI 0.000

Z-score -0.59

OE 1.12 (0.84–1.50)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.65Z-score

OE missense 1.12 (1.01–1.24)

271 obs / 242.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.12 (0.84–1.50)

0≤0.351.4

Missense OE?1.12 (1.01–1.24)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 32 / 28.6Missense obs/exp: 271 / 242.6Syn Z: -0.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAH-related phenylketonuria (PKU)LOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6550th %ile

GOF

0.5464th %ile

LOF

0.3453th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1757 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic462

Likely Pathogenic451

VUS352

Likely Benign369

Benign64

Conflicting15

462

Pathogenic

451

Likely Pathogenic

352

VUS

369

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	248	180	33	1	462
Likely Pathogenic	80	341	28	2	451
VUS	1	260	66	25	352
Likely Benign	0	13	173	183	369
Benign	0	2	54	8	64
Conflicting	—				15
Total	329	796	354	219	1,713

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap PAH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

PAH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — PAH

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Advanced Malignant Solid NeoplasmAnatomic Stage III Breast Cancer AJCC v8Anatomic Stage IV Breast Cancer AJCC v8

Targeted Therapy Directed by Genetic Testing in Treating Patients With Locally Advanced or Advanced Solid Tumors, The ComboMATCH Screening Trial

RECRUITING

NCT05564377Phase PHASE2National Cancer Institute (NCI)Started 2023-04-07

AlpelisibBinimetinibBiopsy Procedure

Diabetes Mellitus, Type 1Inflammation

The Role of the Adrenergic System in Hypoglycaemia Induced Inflammatory Response in People With Type 1 Diabetes and People Without Type 1 Diabetes-RAID-II

ACTIVE NOT RECRUITING

NCT06422494Phase NARadboud University Medical CenterStarted 2025-01-01

hyperinsulinaemic hypoglycaemic clampPropranolol Hydrochloride 1 MG/MLPhentolamine

Acute Myeloid LeukemiaMyelodysplastic Syndrome With Excess Blasts-2

A Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndromes With Excess Blasts-2 With FLT3 Mutations Eligible for Intensive Chemotherapy

ACTIVE NOT RECRUITING

NCT04027309Phase PHASE3Stichting Hemato-Oncologie voor Volwassenen NederlandStarted 2019-12-20

GilteritinibMidostaurin

Breast NeoplasmsTriple Negative Breast NeoplasmsHR Low-Positive/HER2-Negative Breast Neoplasms

A Clinical Study of Sacituzumab Tirumotecan (Sac-TMT, MK-2870) in People With Breast Cancer (MK-2870-032)

RECRUITING

NCT06966700Phase PHASE3Merck Sharp & Dohme LLCStarted 2025-06-30

Sacituzumab tirumotecanPembrolizumabRescue Medication

Ibrutinib, Rituximab, Etoposide, Prednisone, Vincristine Sulfate, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With HIV-Positive Stage II-IV Diffuse Large B-Cell Lymphomas

ACTIVE NOT RECRUITING

NCT03220022Phase PHASE1National Cancer Institute (NCI)Started 2018-03-16

CyclophosphamideDoxorubicin HydrochlorideEtoposide

ALK Gene RearrangementALK Gene TranslocationALK Positive

Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Removed by Surgery and ALK Fusion Mutations (An ALCHEMIST Treatment Trial)

ACTIVE NOT RECRUITING

NCT02201992Phase PHASE3ECOG-ACRIN Cancer Research GroupStarted 2015-03-23

Clinical ObservationCrizotinibLaboratory Biomarker Analysis

Carrier of PhenylketonuriaHealthy

Impact of Phenylalanine Elevations on Brain and Cognition in Adult PKU Carriers

RECRUITING

NCT07220265Phase NAUniversity of Missouri-ColumbiaStarted 2025-12-19

Phenylalanine (Phe)Placebo

Acute Myeloid LeukemiaAML, AdultAML With Gene Mutations

Revumenib in Combination With 7+3 + Midostaurin in AML

RECRUITING

NCT06313437Phase PHASE1Richard Stone, MDStarted 2024-12-06