Is NCF2 p.Val490Met (c.1468G>A) pathogenic?

NCF2 p.Val490Met (c.1468G>A) is classified Uncertain significance in NCF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-21). AlphaMissense: likely pathogenic (0.6227); Very rare (popmax 0.0011%, sas).

How common is NCF2 p.Val490Met (c.1468G>A) in the general population?

NCF2 p.Val490Met (c.1468G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about NCF2 p.Val490Met (c.1468G>A)?

AlphaMissense predicts likely pathogenic (score 0.6227) — an in-silico prediction, not a clinical call.

NCF2 p.Val490Met

c.1468G>A · VCV4923231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6227 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6227	likely pathogenic
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.20	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.77, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 34 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	31.0	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 0.0011% South Asian · 1/91,068 alleles

Overall 6.2e-05% 1/1,613,966 alleles · very rare exomes 1/1,461,744 · genomes 0/152,222 · 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.Val490Met
Coding: c.1468G>A
MANE Select: NM_000433
Type: single nucleotide variant
Location: chr1:183560096 (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 490: the sh3 2 domain; a β-strand

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

Similar variants

NCF2 c.175-1G>A Pathogenic ★★ same type
NCF2 c.257+1G>A Pathogenic/Likely pathogenic ★★ same type
NCF2 c.366+1G>A Pathogenic ★★ same type
NCF2 c.714-2A>G Likely pathogenic ★★ same type
NCF2 p.Ala202Val Pathogenic/Likely pathogenic ★★ same type
NCF2 p.Arg102Ter Pathogenic ★★ same type
NCF2 p.Arg184Ter Pathogenic/Likely pathogenic ★★ same type
NCF2 p.Arg66Ter Pathogenic ★★ same type

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-val490met (accessed [today's date]).

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