Is NCF4 p.Arg8Gln (c.23G>A) pathogenic?

NCF4 p.Arg8Gln (c.23G>A) is classified Uncertain significance in NCF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.5372); Ultra-rare (popmax 0.0119%, sas); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3.

How common is NCF4 p.Arg8Gln (c.23G>A) in the general population?

NCF4 p.Arg8Gln (c.23G>A) is ultra-rare (popmax 0.0119%, 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.Arg8Gln (c.23G>A)?

AlphaMissense predicts ambiguous (score 0.5372) — an in-silico prediction, not a clinical call.

NCF4 p.Arg8Gln

Q: What condition is associated with NCF4 p.Arg8Gln (c.23G>A)?

NCF4 p.Arg8Gln (c.23G>A) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (ClinVar).

c.23G>A · rs762576326 · VCV1499091

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5372 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5372	ambiguous
REVEL	0.12	moderately benign-leaning
SaProt	LLR -5.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.49, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.18 · regional, not allelic
Overall
CADD	33.0	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 0.0119% South Asian · 10/84,054 alleles

Filtering AF 0.0064% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00487%

Overall 0.00413% 64/1,551,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0119%	8,405
Remaining individualsnot grpmax-eligible	0.00499%	20,032
European (non-Finnish)	0.00392%	25,485
Admixed American	0.00392%	25,501
Finnishnot grpmax-eligible	0.00334%	29,933
African / African-American	0.00273%	36,586

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.Arg8Gln
Coding: c.23G>A
MANE Select: NM_000631
dbSNP: rs762576326
Type: single nucleotide variant
Location: chr22:36861194 (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 8: an α-helix

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.Arg8Trp Uncertain significance ★ ⚠ same residue
NCF4 p.Arg8= 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-arg8gln (accessed [today's date]).

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