NOX3

Chr 6

NADPH oxidase 3

Also known as: GP91-3, MOX-2

NCBI Gene: 50508 ENSG00000074771 UniProt: Q9HBY0 OMIM: 607105

This protein is a NADPH oxidase that generates superoxide and other reactive oxygen species, and plays a critical role in the biogenesis of otoconia/otoliths, the crystalline structures in the inner ear involved in gravity perception. Mutations cause autosomal recessive congenital hearing loss with vestibular dysfunction. The gene is highly constrained against loss-of-function variation, indicating that complete loss of NOX3 function is likely incompatible with normal inner ear development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the NOX family of NADPH oxidases. These enzymes have the capacity to generate superoxide and other reactive oxygen species (ROS) and transport electrons across the plasma membrane. The ROS generated by family members have been implicated in numerous biological functions including host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. The protein encoded by this gene is expressed predominantly in the inner ear and is involved in the biogenesis of otoconia/otolith, which are crystalline structures of the inner ear involved in the perception of gravity.[provided by RefSeq, May 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.05

Clinical Summary— NOX3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

88 VUS of 99 total submissions

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Clinical Trials

1 active or recruiting trial — 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?

1.05LOEUF

pLI 0.000

Z-score 1.32

OE 0.76 (0.55–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.23Z-score

OE missense 1.04 (0.95–1.13)

336 obs / 324.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.76 (0.55–1.05)

0≤0.351.4

Missense OE?1.04 (0.95–1.13)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 26 / 34.4Missense obs/exp: 336 / 324.6Syn Z: -1.05

This gene — mechanism propensity

0.6743th %ile

GOF

0.81top 10%

LOF

0.2678th %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

99 submitted variants in ClinVar

ClinVar

Classification Summary

VUS88

Likely Benign4

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	88	0	88
Likely Benign	4	0	4
Benign	0	1	1
Total	92	1	93

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap NOX3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →