Is MSH3 p.Pro657Ala (c.1969C>G) pathogenic?

MSH3 p.Pro657Ala (c.1969C>G) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1174); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro657Ala (c.1969C>G)?

MSH3 p.Pro657Ala (c.1969C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro657Ala (c.1969C>G) in the general population?

MSH3 p.Pro657Ala (c.1969C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH3 p.Pro657Ala (c.1969C>G)?

AlphaMissense predicts likely benign (score 0.1174) — an in-silico prediction, not a clinical call.

MSH3 p.Pro657Ala

c.1969C>G · rs766652796 · VCV1783564

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1174 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1174	likely benign
REVEL	0.55	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: MSH3
Protein: p.Pro657Ala
Coding: c.1969C>G
MANE Select: NM_002439
dbSNP: rs766652796
Type: single nucleotide variant
Location: chr5:80768005 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 657: an α-helix

Full MSH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

MSH3 p.Pro657Leu Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro657Ser Uncertain significance ★★ ⚠ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+1G>A Likely pathogenic ★★ same condition
MSH3 c.1764-1G>A Pathogenic/Likely pathogenic ★★ same condition
MSH3 c.1764-2A>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/msh3-p-pro657ala (accessed [today's date]).

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