Is MSH2 p.Cys697Arg (c.2089T>C) pathogenic?

MSH2 p.Cys697Arg (c.2089T>C) is classified Pathogenic in MSH2 (ClinVar, Expert panel, 8 submitters; last evaluated 2013-09-05). AlphaMissense: likely pathogenic (0.9929); Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MSH2 p.Cys697Arg (c.2089T>C)?

MSH2 p.Cys697Arg (c.2089T>C) is associated with Lynch syndrome, Lynch syndrome 1, Muir-Torre syndrome (ClinVar).

How common is MSH2 p.Cys697Arg (c.2089T>C) in the general population?

MSH2 p.Cys697Arg (c.2089T>C) 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.Cys697Arg (c.2089T>C)?

AlphaMissense predicts likely pathogenic (score 0.9929) — an in-silico prediction, not a clinical call.

MSH2 p.Cys697Arg

c.2089T>C · rs63750961 · VCV90882

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9929 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.9929	likely pathogenic ✓ concordant with ClinVar · top 7% in MSH2
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -15.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	32.0	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

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.Cys697Arg
Coding: c.2089T>C
MANE Select: NM_000251
dbSNP: rs63750961
Type: single nucleotide variant
Location: chr2:47476450 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 697: a UniProt-annotated variant site (in lynch1; decreased mismatch repair activity; loss of protein expression; confers multiple biochemical defects); a UniProt-annotated variant site (in lynch1; has no effect on msh2 splicing); a β-strand

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

Disease context

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

Also linked: Lynch syndrome 1 Muir-Torre syndrome hereditary neoplastic syndrome mismatch repair cancer syndrome 2

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Cys697Phe Pathogenic ★★★ same residue
MSH2 p.Cys697Ter Pathogenic ★★★ same residue
MSH2 p.Cys697Tyr Likely pathogenic ★★★ same residue
MSH2 p.Cys697Trp Likely pathogenic ★★ same residue
MSH2 p.Cys697Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Cys697_Glu698delinsTer Pathogenic ★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T 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-cys697arg (accessed [today's date]).

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