Is MSH2 p.Phe657Cys (c.1970T>G) pathogenic?

MSH2 p.Phe657Cys (c.1970T>G) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-02). AlphaMissense: likely pathogenic (0.644); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Phe657Cys (c.1970T>G)?

MSH2 p.Phe657Cys (c.1970T>G) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH2 p.Phe657Cys (c.1970T>G) in the general population?

MSH2 p.Phe657Cys (c.1970T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Phe657Cys (c.1970T>G)?

AlphaMissense predicts likely pathogenic (score 0.644) — an in-silico prediction, not a clinical call.

MSH2 p.Phe657Cys

c.1970T>G · rs1667249809 · VCV838503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.644 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.644	likely pathogenic
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	27.9	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.Phe657Cys
Coding: c.1970T>G
MANE Select: NM_000251
dbSNP: rs1667249809
Type: single nucleotide variant
Location: chr2:47475235 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 657: the 'interaction with exo1' region; a β-strand

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.Phe657Val Uncertain significance ★★ ⚠ same residue
MSH2 p.Phe657Ile Uncertain significance ★ ⚠ same residue
MSH2 p.Phe657= Benign/Likely benign ★★ same residue
MSH2 p.Phe657Leu 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

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-phe657cys (accessed [today's date]).

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