Is NCF2 p.Pro231Leu (c.692C>T) pathogenic?

NCF2 p.Pro231Leu (c.692C>T) is classified Uncertain significance in NCF2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-23). AlphaMissense: likely benign (0.3074); Ultra-rare (popmax 0.0197%, nfe); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2.

How common is NCF2 p.Pro231Leu (c.692C>T) in the general population?

NCF2 p.Pro231Leu (c.692C>T) is ultra-rare (popmax 0.0197%, 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.

What do computational predictors say about NCF2 p.Pro231Leu (c.692C>T)?

AlphaMissense predicts likely benign (score 0.3074) — an in-silico prediction, not a clinical call.

NCF2 p.Pro231Leu

Q: What condition is associated with NCF2 p.Pro231Leu (c.692C>T)?

NCF2 p.Pro231Leu (c.692C>T) is associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (ClinVar).

c.692C>T · rs144451516 · VCV660978

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.3074	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0197% European (non-Finnish) · 232/1,179,966 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0159% 257/1,614,030 alleles · ultra-rare exomes 247/1,461,822 · genomes 10/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0197%	5,086
Remaining individualsnot grpmax-eligible	0.0128%	7,813
Admixed American	0.00833%	12,004
African / African-American	0.00667%	14,997
East Asian	0.00446%	22,445
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.00312%	32,006

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.Pro231Leu
Coding: c.692C>T
MANE Select: NM_000433
dbSNP: rs144451516
Type: single nucleotide variant
Location: chr1:183569163 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.99 · 7 PDB

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.Pro231= Likely benign ★ 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-pro231leu (accessed [today's date]).

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