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…

Primary Disease Associations & Inheritance

[Hyperphenylalaninemia, non-PKU mild]MIM #261600

PhenylketonuriaMIM #261600

UniProtPhenylalanine hydroxylase deficiency

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · phenylketonuria · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

3495

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.50

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in PAH?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

641 rare PASS variants

Rare truncating (LoF)

1 in 660

118 rare PASS variants

Rare synonymous (reference)

1 in 180

224 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PAH. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 45	1 in 600
South Asian	~43k	1 in 110	1 in 670
Remaining (unassigned)	~30k	1 in 35	1 in 510
European (Finnish)	~27k	1 in 140	1 in 2,000
Admixed American	~22k	1 in 44	1 in 2,500
African / African American	~21k	1 in 110	1 in 860
East Asian	~20k	1 in 56	1 in 470
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 58	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 13 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 13.? see exons ↓