PAH

Chr 12AR

phenylalanine hydroxylase

Also known as: PH, PKU, PKU1

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]

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismARLOEUF 1.502 OMIM phenotypes
VCEP Guidelines: PhenylketonuriaReleased
ClinGen Panel
Clinical SummaryPAH
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Gene-Disease Validity (ClinGen)
phenylketonuria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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
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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

Tolerant — LoF & missense variants common in population
LoF Constraint?
1.50LOEUF
pLI 0.000
Z-score -0.59
OE 1.12 (0.841.50)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?
-0.65Z-score
OE missense 1.12 (1.011.24)
271 obs / 242.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?
LoF OE?1.12 (0.841.50)
00.351.4
Missense OE?1.12 (1.011.24)
00.61.4
Synonymous OE?1.11
01.21.6
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.

DN
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

Classification Summary

Pathogenic462
Likely Pathogenic451
VUS352
Likely Benign369
Benign64
Conflicting15
462
Pathogenic
451
Likely Pathogenic
352
VUS
369
Likely Benign
64
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
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
Total3297963542191,713

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.

Clinical Trials

Active and recruiting trials from 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
AIDS-Related LymphomaAnn Arbor Stage II Diffuse Large B-Cell LymphomaAnn Arbor Stage III Diffuse Large B-Cell Lymphoma

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
RevumenibMidostaurinCytarabine
Large Cell Neuroendocrine Carcinoma of the Lung

FIRST-NEC (GFPC 01-2022) - Combination of Durvalumab With Etoposide and Platinum

RECRUITING
NCT06393816Phase PHASE2Centre Leon BerardStarted 2024-06-13
Durvalumab with etoposide and Carboplatin/Cisplatin
Carcinoma, NeuroendocrineTumor, NeuroendocrineTumors, Neuroendocrine

A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity

RECRUITING
NCT06406465Phase PHASE2National Cancer Institute (NCI)Started 2026-07-14
BelinostatCisplatinEtoposide
Sickle Cell DiseaseDyslipidemiaComplication

Lipid Balance in Adult Sickle Cell Patients

ACTIVE NOT RECRUITING
NCT05780775Phase NACentre Hospitalier Universitaire de la GuadeloupeStarted 2022-11-30
HDL2
AML, ChildhoodAcute Myeloid Leukemia

Clinical Study of Induction Therapy Options Based on Molecular Subtyping and MRD in Children and Adolescents With AML

RECRUITING
NCT06221683Phase PHASE2Children's Hospital of Soochow UniversityStarted 2024-01-01
HomoharringtonineCytarabineEtoposide