PTS

Chr 11AR

6-pyruvoyltetrahydropterin synthase

ENSG00000150787 UniProt: Q03393 OMIM: 612719

The encoded enzyme catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for enzymes involved in serotonin biosynthesis and nitric oxide synthase activity. Mutations cause autosomal recessive hyperphenylalaninemia due to BH4 deficiency. The pathogenic mechanism involves disrupted tetrahydrobiopterin synthesis leading to deficient cofactor availability for critical enzymatic processes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM

Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hyperphenylalaninemia, BH4-deficient, AMIM #261640

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · BH4-deficient hyperphenylalaninemia A · AR · ClinGen 2017

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

2001

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.69

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — PTS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.69LOEUF

pLI 0.000

Z-score 0.07

OE 0.97 (0.57–1.69)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.13Z-score

OE missense 0.96 (0.80–1.16)

76 obs / 79.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.97 (0.57–1.69)

0≤0.351.4

Missense OE?0.96 (0.80–1.16)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 8 / 8.2Missense obs/exp: 76 / 79.1Syn Z: -0.93

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 620

192 rare PASS variants

Rare truncating (LoF)

1 in 3,800

55 rare PASS variants

Rare synonymous (reference)

1 in 580

66 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PTS. 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 700	1 in 3,700
South Asian	~43k	1 in 490	1 in 6,900
Remaining (unassigned)	~30k	1 in 730	1 in 890
European (Finnish)	~27k	1 in 570	1 in 2,200
Admixed American	~22k	1 in 580	1 in 2,300
African / African American	~21k	1 in 270	≈ 1 in 5,600
East Asian	~20k	1 in 240	≈ 1 in 19,000
Ashkenazi Jewish	~13k	≈ 1 in 6,400	none seen
Middle Eastern	~2,884	1 in 570	≈ 1 in 2,800

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): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓