Is NCF2 p.Cys499fs (c.1492_1496dup) pathogenic?

NCF2 p.Cys499fs (c.14921496dup) is classified Uncertain significance in NCF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-12). Very rare (popmax 0.00134%, afr); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

What condition is associated with NCF2 p.Cys499fs (c.1492_1496dup)?

NCF2 p.Cys499fs (c.1492_1496dup) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

How common is NCF2 p.Cys499fs (c.1492_1496dup) in the general population?

NCF2 p.Cys499fs (c.1492_1496dup) is very rare (popmax 0.00134%, afr) (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.Cys499fs

c.1492_1496dup · rs1671770625 · VCV933838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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	escapes	premature termination codon in the last exon (15 of 15) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	GERP -0.23, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,892 alleles

Overall 6.2e-05% 1/1,613,980 alleles · very rare exomes 0/1,461,866 · genomes 1/152,114 · 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.Cys499fs
Coding: c.1492_1496dup
MANE Select: NM_000433
dbSNP: rs1671770625
Type: Duplication
Location: chr1:183556202 (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 499: the sh3 2 domain

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.Lys196fs Pathogenic ★ same condition
NCF2 c.1001-14dup Likely benign ★ same condition
NCF2 c.1026+13_1026+14dup Likely benign ★ same condition
NCF2 c.1469-5_1469-2dup Likely benign ★ same condition
NCF2 c.1469-5_1469-4dup Likely benign ★ same condition
NCF2 c.366+12dup Likely benign ★ same condition
NCF2 c.366+15dup Likely benign ★ same condition
NCF2 p.Lys134fs 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-cys499fs (accessed [today's date]).

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