Is NCF2 p.Ala140fs (c.417del) pathogenic?

NCF2 p.Ala140fs (c.417del) is classified Pathogenic/Likely pathogenic in NCF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-02). Very rare (popmax 8.47e-05%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

How common is NCF2 p.Ala140fs (c.417del) in the general population?

NCF2 p.Ala140fs (c.417del) is very rare (popmax 8.47e-05%, 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.

NCF2 p.Ala140fs

Q: What condition is associated with NCF2 p.Ala140fs (c.417del)?

NCF2 p.Ala140fs (c.417del) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2, chronic granulomatous disease (ClinVar).

c.417del · rs2527964515 · VCV2445914

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,882 · genomes 0/152,310 · joint denominator

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.Ala140fs
Coding: c.417del
MANE Select: NM_000433
dbSNP: rs2527964515
Type: Deletion
Location: chr1:183574571 (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 140: 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

granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: chronic granulomatous disease

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.Lys19_Asp21del Pathogenic ★★ same condition
NCF2 p.Lys391fs Pathogenic ★★ same condition
NCF2 p.Thr279fs Pathogenic ★★ same condition
NCF2 c.258-13del Likely benign ★★ same condition
NCF2 c.855+20del Likely benign ★★ same condition
NCF2 p.Gln367fs Likely pathogenic ★ same condition
NCF2 p.Glu243fs Pathogenic ★ same condition
NCF2 p.Glu480fs Likely 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-ala140fs (accessed [today's date]).

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