Is MSH2 p.Val830Phe (c.2488G>T) pathogenic?

MSH2 p.Val830Phe (c.2488G>T) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely pathogenic (0.9893); Absent from gnomAD v4.1; Associated with Lynch syndrome 1.

What condition is associated with MSH2 p.Val830Phe (c.2488G>T)?

MSH2 p.Val830Phe (c.2488G>T) is associated with Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Val830Phe (c.2488G>T) in the general population?

MSH2 p.Val830Phe (c.2488G>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH2 p.Val830Phe (c.2488G>T)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

MSH2 p.Val830Phe

c.2488G>T · rs2104435779 · VCV2676708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic · top 8% in MSH2
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -15.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Pangolin	Δ0.21	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH2
Protein: p.Val830Phe
Coding: c.2488G>T
MANE Select: NM_000251
dbSNP: rs2104435779
Type: single nucleotide variant
Location: chr2:47480725 (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

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Val830Ala Uncertain significance ★ ⚠ same residue
MSH2 p.Val830Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C Pathogenic ★★★ same condition
MSH2 c.1077-2A>G 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-val830phe (accessed [today's date]).

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