Is NCF2 p.Ala128Val (c.383C>T) pathogenic?

NCF2 p.Ala128Val (c.383C>T) is classified Likely pathogenic in NCF2 (ClinVar, Single submitter, 3 submitters; last evaluated 2026-04-09). AlphaMissense: likely pathogenic (0.9353); Very rare (popmax 0.00329%, sas); Associated with chronic granulomatous disease.

What condition is associated with NCF2 p.Ala128Val (c.383C>T)?

NCF2 p.Ala128Val (c.383C>T) is associated with chronic granulomatous disease, granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

How common is NCF2 p.Ala128Val (c.383C>T) in the general population?

NCF2 p.Ala128Val (c.383C>T) is very rare (popmax 0.00329%, 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 NCF2 p.Ala128Val (c.383C>T)?

AlphaMissense predicts likely pathogenic (score 0.9353) — an in-silico prediction, not a clinical call.

NCF2 p.Ala128Val

c.383C>T · rs119103274 · VCV2246

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9353 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chronic granulomatous disease

Computational evidence

Protein change
AlphaMissense	0.9353	likely pathogenic ✓ concordant with ClinVar · top 9% in NCF2
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -14.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	27.7	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,614,024 alleles · very rare exomes 2/1,461,872 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
African / African-American	0.00134%	74,902

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.Ala128Val
Coding: c.383C>T
MANE Select: NM_000433
dbSNP: rs119103274
Type: single nucleotide variant
Location: chr1:183574605 (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 128: a UniProt-annotated variant site (in cgd2); an α-helix

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

Disease context

chronic granulomatous disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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.Ala128= Likely benign ★ 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.Arg102Ter Pathogenic ★★ same condition
NCF2 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same condition
NCF2 p.Arg66Ter 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-ala128val (accessed [today's date]).

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