NOX4

Chr 11

NADPH oxidase 4

Also known as: KOX, KOX-1, RENOX

NCBI Gene: 50507 ENSG00000086991 UniProt: Q9NPH5

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.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the NOX-family of enzymes that functions as the catalytic subunit the NADPH oxidase complex. The encoded protein is localized to non-phagocytic cells where it acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in numerous biological functions including signal transduction, cell differentiation and tumor cell growth. A pseudogene has been identified on the other arm of chromosome 11. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]

ResearchGenerating clinical summary…

Active trials

598

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.14

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.85 (0.64–1.14)

0≤0.351.4

Missense OE?1.15 (1.05–1.25)

0≤0.61.4

Synonymous OE?1.41

0≤1.21.6

LoF obs/exp: 33 / 38.8Missense obs/exp: 340 / 296.5Syn Z: -3.37

Background carrier burden — how many people carry a rare variant somewhere in NOX4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

777 rare PASS variants

Rare truncating (LoF)

1 in 1,100

125 rare PASS variants

Rare synonymous (reference)

1 in 120

295 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NOX4. 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 92	1 in 1,400
South Asian	~43k	1 in 59	1 in 350
Remaining (unassigned)	~30k	1 in 65	1 in 750
European (Finnish)	~27k	1 in 180	≈ 1 in 8,900
Admixed American	~22k	1 in 94	1 in 1,400
African / African American	~21k	1 in 55	1 in 690
East Asian	~20k	1 in 68	1 in 870
Ashkenazi Jewish	~13k	1 in 210	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 110	≈ 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): 10 of 18 coding exons well covered in gnomAD exomes; exons 6, 7, 8, 11, 12 and 3 more marginal. Genomes: all 18.? see exons ↓