Is NCF4 p.Val95Met (c.283G>A) pathogenic?

NCF4 p.Val95Met (c.283G>A) is classified Conflicting classifications of pathogenicity in NCF4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-15). AlphaMissense: likely benign (0.092); Very rare (popmax 0.00439%, sas); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

How common is NCF4 p.Val95Met (c.283G>A) in the general population?

NCF4 p.Val95Met (c.283G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

How is Chronic granulomatous disease inherited?

Typically Autosomal recessive, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NCF4 p.Val95Met (c.283G>A)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

NCF4 p.Val95Met

Q: What condition is associated with NCF4 p.Val95Met (c.283G>A)?

NCF4 p.Val95Met (c.283G>A) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (ClinVar).

c.283G>A · rs112273712 · VCV2198294

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -2.6
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.18 · regional, not allelic
Overall
CADD	0.053	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,094 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000805% 13/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,773
European (non-Finnish)	0.000763%	131,115

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NCF4
Protein: p.Val95Met
Coding: c.283G>A
MANE Select: NM_000631
dbSNP: rs112273712
Type: single nucleotide variant
Location: chr22:36867403 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.48 · 6 PDB
Residue 95: the px domain

Full NCF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Chronic granulomatous disease (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NCF4 c.118-1G>A Pathogenic/Likely pathogenic ★★ same condition
NCF4 c.759-40C>T Pathogenic ★★ same condition
NCF4 p.Arg105Gln Pathogenic ★★ same condition
NCF4 c.758+24C>T Uncertain significance ★★ same condition
NCF4 c.758+32G>A Uncertain significance ★★ same condition
NCF4 c.758+39T>A Uncertain significance ★★ same condition
NCF4 c.758+51G>A Uncertain significance ★★ same condition
NCF4 c.758+62C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ncf4-p-val95met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown