Is NCF2 p.Pro253Ser (c.757C>T) pathogenic?

NCF2 p.Pro253Ser (c.757C>T) is classified Uncertain significance in NCF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: ambiguous (0.5323); Very rare (popmax 0.000763%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NCF2 p.Pro253Ser (c.757C>T)?

NCF2 p.Pro253Ser (c.757C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NCF2 p.Pro253Ser (c.757C>T) in the general population?

NCF2 p.Pro253Ser (c.757C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about NCF2 p.Pro253Ser (c.757C>T)?

AlphaMissense predicts ambiguous (score 0.5323) — an in-silico prediction, not a clinical call.

NCF2 p.Pro253Ser

c.757C>T · rs1000185935 · VCV2400413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5323 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5323	ambiguous
REVEL	0.513	indeterminate
SaProt	LLR -10.13	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	27.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,180,020 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,934 alleles · very rare exomes 8/1,461,866 · genomes 1/152,068 · 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.Pro253Ser
Coding: c.757C>T
MANE Select: NM_000433
dbSNP: rs1000185935
Type: single nucleotide variant
Location: chr1:183567302 (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 253: the sh3 1 domain

Full NCF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NCF2 p.Pro253= Likely benign ★ same residue
NCF2 p.Ala17Thr Uncertain significance ★★ ⚠ same condition
NCF2 p.Arg38Trp Uncertain significance ★★ ⚠ same condition
NCF2 p.Arg397Gln Uncertain significance ★★ ⚠ same condition
NCF2 p.Arg397Trp Uncertain significance ★★ ⚠ same condition
NCF2 p.Asp412Glu Uncertain significance ★★ ⚠ same condition
NCF2 p.Asp446Tyr Uncertain significance ★★ ⚠ same condition
NCF2 p.Pro320Ala Uncertain significance ★★ ⚠ 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-pro253ser (accessed [today's date]).

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