NCF4

Chr 22AR

neutrophil cytosolic factor 4

Also known as: CGD3, NCF, P40PHOX, SH3PXD4

NCBI Gene: 4689 ENSG00000100365 UniProt: Q15080 OMIM: 601488

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.201 OMIM phenotype

Clinical Summary— NCF4

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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

27 unique Pathogenic / Likely Pathogenic· 176 VUS of 444 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NCF4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.000

Z-score 0.95

OE 0.75 (0.49–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.23Z-score

OE missense 1.04 (0.93–1.17)

215 obs / 205.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.75 (0.49–1.20)

0≤0.351.4

Missense OE?1.04 (0.93–1.17)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 13 / 17.3Missense obs/exp: 215 / 205.8Syn Z: -1.41

This gene — mechanism propensity

0.6259th %ile

GOF

0.6345th %ile

LOF

0.3162th %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

444 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic12

VUS176

Likely Benign174

Benign48

Conflicting8

Pathogenic

Likely Pathogenic

176

VUS

174

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	1	0	0	15
Likely Pathogenic	10	1	1	0	12
VUS	4	163	8	1	176
Likely Benign	0	7	71	96	174
Benign	0	1	39	8	48
Conflicting	—				8
Total	28	173	119	105	433

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap NCF4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →