Is NCF4 p.Ala256= (c.768G>A) pathogenic?

NCF4 p.Ala256= (c.768G>A) is classified Conflicting classifications of pathogenicity in NCF4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-23). Very rare (popmax 0.000594%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

How common is NCF4 p.Ala256= (c.768G>A) in the general population?

NCF4 p.Ala256= (c.768G>A) is very rare (popmax 0.000594%, nfe) (gnomAD).

How is Chronic granulomatous disease inherited?

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

NCF4 p.Ala256=

Q: What condition is associated with NCF4 p.Ala256= (c.768G>A)?

NCF4 p.Ala256= (c.768G>A) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (ClinVar).

c.768G>A · rs766525712 · VCV1391298

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.101	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -2.9
Overall
CADD	0.077	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,178,968 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,612,632 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,518
Finnishnot grpmax-eligible	0.00156%	63,982
European (non-Finnish)grpmax	0.000594%	168,424

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala256=
Coding: c.768G>A
MANE Select: NM_000631
dbSNP: rs766525712
Type: single nucleotide variant
Location: chr22:36876038 (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 256: the pb1 domain; a β-strand

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 p.Ala256Val Uncertain significance ★ ⚠ same residue
NCF4 p.Ala256Thr Likely benign ★ same residue
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

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-ala256 (accessed [today's date]).

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