Is MSH2 p.Val830Ala (c.2489T>C) pathogenic?

MSH2 p.Val830Ala (c.2489T>C) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-06-13). AlphaMissense: likely pathogenic (0.9606); Very rare (popmax 0.000254%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Val830Ala (c.2489T>C)?

MSH2 p.Val830Ala (c.2489T>C) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH2 p.Val830Ala (c.2489T>C) in the general population?

MSH2 p.Val830Ala (c.2489T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Val830Ala (c.2489T>C)?

AlphaMissense predicts likely pathogenic (score 0.9606) — an in-silico prediction, not a clinical call.

MSH2 p.Val830Ala

c.2489T>C · rs1553370328 · VCV455564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.9606	likely pathogenic
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -11.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000254% European (non-Finnish) · 3/1,180,020 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,152 alleles · very rare exomes 3/1,461,828 · genomes 0/152,324 · 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: MSH2
Protein: p.Val830Ala
Coding: c.2489T>C
MANE Select: NM_000251
dbSNP: rs1553370328
Type: single nucleotide variant
Location: chr2:47480726 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 830: an α-helix

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH2 p.Val830Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Val830Phe Uncertain significance ★ ⚠ same residue
MSH2 c.1276+2T>C Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1277-1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1510+1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1510+2T>C Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1661+2T>C Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1661+2T>G Pathogenic/Likely 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/msh2-p-val830ala (accessed [today's date]).

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