Is NCF2 p.Leu248= (c.742C>T) pathogenic?

NCF2 p.Leu248= (c.742C>T) is classified Likely benign in NCF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-23). Ultra-rare (popmax 0.011%, sas); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

How common is NCF2 p.Leu248= (c.742C>T) in the general population?

NCF2 p.Leu248= (c.742C>T) is ultra-rare (popmax 0.011%, 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.

NCF2 p.Leu248=

Q: What condition is associated with NCF2 p.Leu248= (c.742C>T)?

NCF2 p.Leu248= (c.742C>T) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

c.742C>T · rs762714261 · VCV2725887

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.6, phastCons 1
Overall
CADD	6.367	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,090 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000743% 12/1,614,100 alleles · ultra-rare exomes 12/1,461,866 · genomes 0/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,109
Remaining individualsnot grpmax-eligible	0.0032%	31,256

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.Leu248=
Coding: c.742C>T
MANE Select: NM_000433
dbSNP: rs762714261
Type: single nucleotide variant
Location: chr1:183567317 (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 248: the sh3 1 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.Leu248Arg Uncertain significance ★ ⚠ 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-leu248 (accessed [today's date]).

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