NOX4

Chr 11

NADPH oxidase 4

Also known as: KOX, KOX-1, RENOX

NCBI Gene: 50507ENSG00000086991UniProt: Q9NPH5OMIM: 605261

The encoded protein is a NADPH oxidase that catalyzes the reduction of oxygen to hydrogen peroxide and superoxide, functioning as an oxygen sensor in non-phagocytic cells and regulating processes including potassium channel activity and gene expression. NOX4 mutations cause developmental delay with or without dysmorphic facies and neuropathy, inherited in an autosomal recessive pattern. This gene is not highly constrained against loss-of-function variation.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.14
Clinical Summary— NOX4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
18 unique Pathogenic / Likely Pathogenic· 78 VUS of 123 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.14LOEUF
pLI 0.000
Z-score 0.86
OE 0.85 (0.64–1.14)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.90Z-score
OE missense 1.15 (1.05–1.25)
340 obs / 296.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.85 (0.64–1.14)
0≤0.351.4
Missense OE1.15 (1.05–1.25)
0≤0.61.4
Synonymous OE1.41
0≤1.21.6
LoF obs/exp: 33 / 38.8Missense obs/exp: 340 / 296.5Syn Z: -3.37
DN
0.6744th %ile
GOF
0.77top 25%
LOF
0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

123 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic2
VUS78
Likely Benign7
Benign4
16
Pathogenic
2
Likely Pathogenic
78
VUS
7
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
16
0
16
Likely Pathogenic
0
0
2
0
2
VUS
0
73
5
0
78
Likely Benign
0
3
2
2
7
Benign
0
2
1
1
4
Total078263107

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

View in ClinVar →

Protein Context — Lollipop Plot

NOX4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RIPK3 Inhibition Mitigates Denervated Muscle Atrophy via NOX4-Mediated Mitochondrial Restoration and Inflammation Suppression.
Shen Y et al.·J Cachexia Sarcopenia Muscle
2026
TIGAR overexpression alleviates intracerebral hemorrhage injury in mice by suppressing ATF4/NOX4/p22phox-mediated oxidative stress and inflammation.
Li YY et al.·Acta Pharmacol Sin
2026
Mesenchymal Stem Cell and Secretome Treatments Inhibit the mTOR-NOX4 Pathway in Diabetic Kidney Disease.
Njeim R et al.·Diabetes
2026
Vaccarin Improves Myocardial Ischemia-Reperfusion Injury by Attenuating Oxidative Stress and Ferroptosis Through Reducing NOX4-Modulated JAK2/STAT3 Pathway Activation.
Yang H et al.·Kaohsiung J Med Sci
2026
BRD4 Inhibition alleviates sepsis-associated acute kidney injury via suppression of NOX4-mediated oxidative stress and inflammation.
Jia J et al.·Cell Death Discov
2026
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients