Is NCF2 p.Arg102Gln (c.305G>A) pathogenic?

NCF2 p.Arg102Gln (c.305G>A) is classified Uncertain significance in NCF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-11). AlphaMissense: likely pathogenic (0.8017); Ultra-rare (popmax 0.0134%, eas); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

How common is NCF2 p.Arg102Gln (c.305G>A) in the general population?

NCF2 p.Arg102Gln (c.305G>A) is ultra-rare (popmax 0.0134%, eas) (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 NCF2 p.Arg102Gln (c.305G>A)?

AlphaMissense predicts likely pathogenic (score 0.8017) — an in-silico prediction, not a clinical call.

NCF2 p.Arg102Gln

Q: What condition is associated with NCF2 p.Arg102Gln (c.305G>A)?

NCF2 p.Arg102Gln (c.305G>A) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

c.305G>A · rs137854515 · VCV1020940

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8017 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2

Computational evidence

Protein change
AlphaMissense	0.8017	likely pathogenic
REVEL	0.661	pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,890 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00118% 19/1,613,952 alleles · ultra-rare exomes 17/1,461,800 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
Admixed American	0.00333%	29,998
South Asian	0.00329%	30,359
European (non-Finnish)	0.000678%	147,496

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: NCF2
Protein: p.Arg102Gln
Coding: c.305G>A
MANE Select: NM_000433
dbSNP: rs137854515
Type: single nucleotide variant
Location: chr1:183577660 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.99 · 7 PDB
Residue 102: a UniProt-annotated variant site (in cgd2); a turn

Full NCF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 — 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

NCF2 p.Arg102Ter Pathogenic ★★ same residue
NCF2 c.257+1G>A Pathogenic/Likely pathogenic ★★ same condition
NCF2 c.366+1G>A Pathogenic ★★ same condition
NCF2 c.714-2A>G Likely pathogenic ★★ same condition
NCF2 p.Ala202Val Pathogenic/Likely pathogenic ★★ same condition
NCF2 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same condition
NCF2 p.Arg66Ter Pathogenic ★★ same condition
NCF2 p.Arg77Ter Pathogenic ★★ 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/ncf2-p-arg102gln (accessed [today's date]).

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