PNPO

Chr 17AR

pyridoxamine 5'-phosphate oxidase

Also known as: HEL-S-302, PDXPO

NCBI Gene: 55163ENSG00000108439UniProt: Q9NVS9

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]

Primary Disease Associations & Inheritance

Pyridoxamine 5'-phosphate oxidase deficiencyMIM #610090
AR
UniProtPyridoxine-5'-phosphate oxidase deficiency
406
ClinVar variants
51
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— PNPO
🧬
Gene-Disease Validity (ClinGen)
pyridoxal phosphate-responsive seizures · 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.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 160 VUS of 406 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
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.
1.44LOEUF
pLI 0.000
Z-score 0.33
OE 0.90 (0.59–1.44)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?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.
0.78Z-score
OE missense 0.82 (0.70–0.95)
120 obs / 146.6 exp
Tolerant

Mild missense constraint

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.0.90 (0.59–1.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.70–0.95)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 13 / 14.4Missense obs/exp: 120 / 146.6Syn Z: 0.37

ClinVar Variant Classifications

406 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic22
VUS160
Likely Benign158
Benign24
Conflicting13
29
Pathogenic
22
Likely Pathogenic
160
VUS
158
Likely Benign
24
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
5
14
0
29
Likely Pathogenic
8
9
5
0
22
VUS
1
120
37
2
160
Likely Benign
1
1
71
85
158
Benign
0
0
21
3
24
Conflicting
—13
Total2013514890406

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PNPO · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PNPO-related neonatal encephalopathy responsive to pyridoxal-5'-phosphate

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pyridoxamine 5'-phosphate oxidase deficiency

MIM #610090

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PNPO
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Disorders affecting vitamin B(6) metabolism.
Wilson MP et al.·J Inherit Metab Dis
2019Review
PNPO-Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β-Catenin Pathway.
Deng Z et al.·Adv Sci (Weinh)
2025
Effectiveness of Pyridoxal-5'-Phosphate in PNPO Deficiency: A Systematic Review.
Stolwijk NN et al.·J Inherit Metab Dis
2025Review
Characterization of 13 Novel Genetic Variants in Genes Associated with Epilepsy: Implications for Targeted Therapeutic Strategies.
Andjelkovic M et al.·Mol Diagn Ther
2024
Mouse models for inherited monoamine neurotransmitter disorders.
Thöny B et al.·J Inherit Metab Dis
2024Review
Analysis for variable manifestations and molecular characteristics of pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency.
Jiao X et al.·Hum Mol Genet
2023
Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.
Mills PB et al.·Brain
2014
Pyridoxine-5'-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g>A (P.·Arg116gln) mutation.
di Salvo ML et al.·Mol Genet Metab
2017Case report
Pyridox (am) ine 5'-phosphate oxidase deficiency induces seizures in Drosophila melanogaster.
Chi W et al.·Hum Mol Genet
2019
Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes.
Chi W et al.·Proc Natl Acad Sci U S A
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools