Is MSH2 p.Phe657Val (c.1969T>G) pathogenic?

MSH2 p.Phe657Val (c.1969T>G) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-12). AlphaMissense: ambiguous (0.5588); Very rare (popmax 0.000678%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Phe657Val (c.1969T>G)?

MSH2 p.Phe657Val (c.1969T>G) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Phe657Val (c.1969T>G) in the general population?

MSH2 p.Phe657Val (c.1969T>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Phe657Val (c.1969T>G)?

AlphaMissense predicts ambiguous (score 0.5588) — an in-silico prediction, not a clinical call.

MSH2 p.Phe657Val

c.1969T>G · rs1326883188 · VCV1969862

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5588 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.5588	ambiguous
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -8.16	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.92, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	27.0	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 0.000678% European (non-Finnish) · 8/1,179,990 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,870 alleles · very rare exomes 7/1,461,736 · genomes 1/152,134 · 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.Phe657Val
Coding: c.1969T>G
MANE Select: NM_000251
dbSNP: rs1326883188
Type: single nucleotide variant
Location: chr2:47475234 (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

Also linked: hereditary neoplastic syndrome

Similar variants

MSH2 p.Phe657= Benign/Likely benign ★★ same residue
MSH2 p.Phe657Cys Uncertain significance ★ ⚠ same residue
MSH2 p.Phe657Ile Uncertain significance ★ ⚠ same residue
MSH2 p.Phe657Leu Uncertain significance ★ ⚠ 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

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-phe657val (accessed [today's date]).

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