PAH

Chr 12

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]

Primary Disease Associations & Inheritance

UniProtPhenylalanine hydroxylase deficiency
0
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
12
Active trials
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
Some data sources returned errors (2)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.65Z-score
OE missense 1.12 (1.011.24)
271 obs / 242.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.12 (0.841.50)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.12 (1.011.24)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
01.21.6
LoF obs/exp: 32 / 28.6Missense obs/exp: 271 / 242.6Syn Z: -0.83

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.

Gene2Phenotype Curations

PAH-related phenylketonuria (PKU)

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

Acute Myeloid Leukemia

Comparing Cytarabine + Daunorubicin Therapy Versus Cytarabine + Daunorubicin + Venetoclax Versus Venetoclax + Azacitidine in Younger Patients With Intermediate Risk AML (A MyeloMATCH Treatment Trial)

RECRUITING
NCT05554393Phase PHASE2National Cancer Institute (NCI)Started 2024-09-13
AzacitidineBiospecimen CollectionBone Marrow Aspiration
Stage IB Lung Non-Small Cell Carcinoma AJCC v7Stage II Lung Non-Small Cell Cancer AJCC v7Stage IIIA Lung Non-Small Cell Cancer AJCC v7

Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial)

ACTIVE NOT RECRUITING
NCT02595944Phase PHASE3National Cancer Institute (NCI)Started 2016-07-22
Biospecimen CollectionComputed TomographyEchocardiography Test
GanglioneuroblastomaHigh Risk Neuroblastoma

Dinutuximab, Sargramostim, and Combination Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma

ACTIVE NOT RECRUITING
NCT03786783Phase PHASE2National Cancer Institute (NCI)Started 2019-03-04
Autologous Hematopoietic Stem Cell TransplantationCarboplatinCisplatin
Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17
AdavosertibAfatinibAfatinib Dimaleate
ThymomaThymic CarcinomaClinical Masaoka Stage II to IVA

Chemotherapy Plus Cetuximab Followed by Surgical Resection in Patients With Locally Advanced or Recurrent Thymoma or Thymic Carcinoma

ACTIVE NOT RECRUITING
NCT01025089Phase PHASE2Memorial Sloan Kettering Cancer CenterStarted 2009-12
Cetuximab, Cisplatin, Doxorubicin & Cyclophosphamide
Acute Myeloid LeukemiaAcute Myeloid Leukemia Arising From Previous Myelodysplastic SyndromeAcute Myeloid Leukemia Arising From Previous Myeloproliferative Neoplasm

Testing the Use of Combination Therapy in Patients With Persistent Low Level Acute Myeloid Leukemia Following Initial Treatment, The ERASE Study (A MyeloMATCH Treatment Trial)

NOT YET RECRUITING
NCT05554419Phase PHASE2National Cancer Institute (NCI)Started 2026-07-01
AzacitidineBone Marrow Aspiration and BiopsyCytarabine
Scrub Typhus

Scrub Typhus Antibiotic Resistance Trial

RECRUITING
NCT03083197Phase PHASE4University of OxfordStarted 2017-10-15
Doxycycline 7 daysDoxycycline 3 daysAzithromycin 3 days
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®
Opioid Use DisorderPregnancy Related

Predicting and Preventing Adverse Maternal and Child Outcomes of Opioid Use Disorder in Pregnancy

RECRUITING
NCT05942313Ilana HullStarted 2023-08-28
Buprenorphine/ Methadone exposure
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
Stage IB Lung Non-Small Cell Carcinoma AJCC v7Stage II Lung Non-Small Cell Cancer AJCC v7Stage IIA Lung Cancer AJCC v8

Genetic Testing in Screening Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

ACTIVE NOT RECRUITING
NCT02194738Phase NANational Cancer Institute (NCI)Started 2014-09-26
Biospecimen CollectionCarboplatinCisplatin
Ganglioneuroblastoma, NodularNeuroblastoma

Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma

RECRUITING
NCT06172296Phase PHASE3National Cancer Institute (NCI)Started 2024-04-19
Biospecimen CollectionBone Marrow AspirationBone Marrow Biopsy