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]

OMIMResearchGenerating clinical summary…
LOFmechanismARLOEUF 1.502 OMIM phenotypes
VCEP Guidelines: PhenylketonuriaReleased
ClinGen Panel
Clinical SummaryPAH
🧬
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.
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

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

0 submitted variants in ClinVar

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

Phenylketonurias

Nutritional Impacts of Palynziq on Patients With Phenylketonuria (PKU)

RECRUITING
NCT04404530Emory UniversityStarted 2019-10-08
Palynziq
AIDS-Related Burkitt LymphomaAIDS-Related Diffuse Large B-cell LymphomaAIDS-Related Plasmablastic Lymphoma

Gene Therapy and Combination Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma

ACTIVE NOT RECRUITING
NCT02337985Phase PHASE1City of Hope Medical CenterStarted 2015-11-20
PrednisoneRituximabEtoposide
Breast Cancer

First-line Gemcitabine Plus Cisplatin in Locally Advanced (IIIC Stage) Breast Cancer Patients

ACTIVE NOT RECRUITING
NCT06531447Phase PHASE2The National Center of Oncology, AzerbaijanStarted 2014-05
CisplatinGemcitabineDoxorubicin
Portopulmonary HypertensionPulmonary Arterial Hypertension (PAH)Congenital Portosystemic Shunt

Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension

NOT YET RECRUITING
NCT07314814Prof. Valérie Mc LinStarted 2026-02-01
targeted gene panels analysiswhole genome analysis
Sarcoma

Bevacizumab/Doxorubicin/Radiation for Sarcoma

ACTIVE NOT RECRUITING
NCT01746238Phase PHASE1Massachusetts General HospitalStarted 2013-03
BevacizumabDoxorubicinRadiation Therapy
Acute Lymphoid LeukemiaMinimal Residual DiseaseGene Abnormality

Adult Acute Lymphoblastic Leukemia Treated With Pediatric Regimen in Brazil

RECRUITING
NCT05959720Instituto do Cancer do Estado de São PauloStarted 2023-09-05
PrednisoneVincristinDaunorubicin
Inflammatory Breast Cancer (IBC)

Study Of Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer

ACTIVE NOT RECRUITING
NCT02876302Phase PHASE2Dana-Farber Cancer InstituteStarted 2018-01-24
RuxolitinibPaclitaxelDoxorubicin
Previously Treated Non-Small Cell Lung Cancer

Lung-MAP: A Master Screening Protocol for Previously-Treated Non-Small Cell Lung Cancer

RECRUITING
NCT03851445Phase PHASE2, PHASE3SWOG Cancer Research NetworkStarted 2019-02-06
Screening Platform
Pulmonary HypertensionPulmonary Arterial HypertensionPulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)

Rutgers University Study of the Genetics of Pulmonary Hypertension

RECRUITING
NCT07217522Rutgers, The State University of New JerseyStarted 2025-08-23
Saliva sampleHealth surveys
Endometrial AdenocarcinomaEndometrial Mixed Cell AdenocarcinomaEndometrial Serous Adenocarcinoma

Testing the Combination of Olaparib and Durvalumab, Cediranib and Durvalumab, Olaparib and Capivasertib, and Cediranib Alone in Recurrent or Refractory Endometrial Cancer Following the Earlier Phase of the Study That Tested Olaparib and Cediranib in Comparison to Cediranib Alone, and Olaparib Alone

ACTIVE NOT RECRUITING
NCT03660826Phase PHASE2National Cancer Institute (NCI)Started 2018-09-27
Biospecimen CollectionBone Marrow AspirateBone Marrow Biopsy
Brain and Central Nervous System Tumors

Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma

ACTIVE NOT RECRUITING
NCT00602667Phase PHASE2St. Jude Children's Research HospitalStarted 2007-12-17
Induction ChemotherapyLow-Risk TherapyHigh-Risk Therapy
IGF1 Deficiency

Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).

RECRUITING
NCT00903110Esteve Pharmaceuticals, S.A.Started 2008-12-09
Increlex®