PNPO

Chr 17AR

pyridoxamine 5'-phosphate oxidase

Also known as: HEL-S-302, PDXPO

NCBI Gene: 55163 ENSG00000108439 UniProt: Q9NVS9 OMIM: 603287

This enzyme catalyzes the oxidation of pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate into pyridoxal 5'-phosphate (vitamin B6), which serves as an essential cofactor for neurotransmitter synthesis and homocysteine metabolism. Mutations cause pyridoxamine 5'-phosphate oxidase deficiency, a form of neonatal epileptic encephalopathy with autosomal recessive inheritance. The gene shows minimal constraint against loss-of-function variants, consistent with the recessive disease pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5'-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy. [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Pyridoxamine 5'-phosphate oxidase deficiencyMIM #610090

UniProtPyridoxine-5'-phosphate oxidase deficiency

Clinical highlights

Management implications

Responds to pyridoxal-5-phosphate (and some to pyridoxine); untreated it is severe.Treat empirically with PLP in neonatal epileptic encephalopathy — the difference is life-altering.

PNPO: treatable — pyridoxal-5'-phosphate

Gene–disease validity (ClinGen)

Definitive · pyridoxal phosphate-responsive seizures · 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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.44

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — PNPO

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Treatment implicationsTreatable

PNPO deficiency (pyridoxal-5-phosphate-dependent epilepsy)

Treat empirically with PLP in neonatal epileptic encephalopathy — the difference is life-altering.

Responds to pyridoxal-5-phosphate (and some to pyridoxine); untreated it is severe.

Treatment of choice

pyridoxal-5'-phosphate (PLP)

Mills et al. 2014, Brain. Confirm with a neurologist and current guidelines. Functional class (GOF/LOF) is from published functional/segregation data, never inferred from the variant. As of 2026-10. Curated from the clinical genetics/neurology literature (cited per gene). Decision-support, not prescribing.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.44LOEUF

pLI 0.000

Z-score 0.33

OE 0.90 (0.59–1.44)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.78Z-score

OE missense 0.82 (0.70–0.95)

120 obs / 146.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.90 (0.59–1.44)

0≤0.351.4

Missense OE?0.82 (0.70–0.95)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 13 / 14.4Missense obs/exp: 120 / 146.6Syn Z: 0.37

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 270

305 rare PASS variants

Rare truncating (LoF)

1 in 2,900

66 rare PASS variants

Rare synonymous (reference)

1 in 610

121 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PNPO. 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 320	1 in 3,300
South Asian	~43k	1 in 140	1 in 2,500
Remaining (unassigned)	~30k	1 in 280	1 in 3,700
European (Finnish)	~27k	1 in 1,600	1 in 2,200
Admixed American	~22k	1 in 220	1 in 3,200
African / African American	~21k	1 in 170	1 in 1,900
East Asian	~20k	1 in 170	1 in 2,000
Ashkenazi Jewish	~13k	≈ 1 in 3,300	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 190	≈ 1 in 1,400

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 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓