NCF4
Chr 22ARneutrophil cytosolic factor 4
Also known as: CGD3, NCF, P40PHOX, SH3PXD4
The protein is a cytosolic regulatory subunit of the phagocyte NADPH oxidase complex that mediates electron transfer from NADPH to oxygen to produce superoxide anions essential for antimicrobial host defense. Mutations cause chronic granulomatous disease, an autosomal recessive primary immunodeficiency characterized by recurrent severe bacterial and fungal infections due to defective neutrophil killing of pathogens. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern where both copies must be affected to cause disease.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
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.
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
465 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 14 | 1 | 16 | 0 | 31 |
Likely Pathogenic | 9 | 1 | 2 | 0 | 12 |
VUS | 4 | 163 | 10 | 1 | 178 |
Likely Benign | 0 | 8 | 72 | 96 | 176 |
Benign | 0 | 1 | 39 | 8 | 48 |
Conflicting | — | 9 | |||
| Total | 27 | 174 | 139 | 105 | 454 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
NCF4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools