Is NCF2 p.Lys508fs (c.1523_1524del) pathogenic?

NCF2 p.Lys508fs (c.15231524del) is classified Uncertain significance in NCF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-06). Very rare (popmax 0.000169%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

What condition is associated with NCF2 p.Lys508fs (c.1523_1524del)?

NCF2 p.Lys508fs (c.1523_1524del) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

How common is NCF2 p.Lys508fs (c.1523_1524del) in the general population?

NCF2 p.Lys508fs (c.1523_1524del) is very rare (popmax 0.000169%, 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.Lys508fs

c.1523_1524del · rs772569356 · VCV1905916

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 0.000169%, 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	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 5.9	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,036 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,204 alleles · very rare exomes 2/1,461,882 · genomes 0/152,322 · 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.Lys508fs
Coding: c.1523_1524del
MANE Select: NM_000433
dbSNP: rs772569356
Type: Deletion
Location: chr1:183556175 (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 508: the sh3 2 domain; 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

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.Lys508Arg Uncertain significance ★ ⚠ same residue
NCF2 p.Ala140fs Pathogenic/Likely pathogenic ★★ same condition
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

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-lys508fs (accessed [today's date]).

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