Is NCF2 p.Arg66= (c.196C>A) pathogenic?

NCF2 p.Arg66= (c.196C>A) is classified Conflicting classifications of pathogenicity in NCF2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-15). Very rare (popmax 0.0022%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

How common is NCF2 p.Arg66= (c.196C>A) in the general population?

NCF2 p.Arg66= (c.196C>A) is very rare (popmax 0.0022%, 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.Arg66=

Q: What condition is associated with NCF2 p.Arg66= (c.196C>A)?

NCF2 p.Arg66= (c.196C>A) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

c.196C>A · rs750782115 · VCV875336

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, 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.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP -1.1, phastCons 1
Overall
CADD	8.941	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,179,974 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00173% 28/1,613,990 alleles · very rare exomes 25/1,461,784 · genomes 3/152,206 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)grpmax	0.0022%	45,384
Remaining individualsnot grpmax-eligible	0.0016%	62,474

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg66=
Coding: c.196C>A
MANE Select: NM_000433
dbSNP: rs750782115
Type: single nucleotide variant
Location: chr1:183586956 (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 66: 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.Arg66Ter Pathogenic ★★ same residue
NCF2 p.Arg66Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
NCF2 p.Arg66fs Likely pathogenic ★ 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

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-arg66 (accessed [today's date]).

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