Is MSH3 p.Ala65Pro (c.193G>C) pathogenic?

MSH3 p.Ala65Pro (c.193G>C) is classified Benign/Likely benign in MSH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.0727); Rare (popmax 0.102%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Ala65Pro (c.193G>C)?

MSH3 p.Ala65Pro (c.193G>C) is associated with hereditary neoplastic syndrome, endometrial carcinoma, familial adenomatous polyposis 4 (ClinVar).

How common is MSH3 p.Ala65Pro (c.193G>C) in the general population?

MSH3 p.Ala65Pro (c.193G>C) is rare (popmax 0.102%, eas) (gnomAD).

What do computational predictors say about MSH3 p.Ala65Pro (c.193G>C)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

MSH3 p.Ala65Pro

c.193G>C · rs774328125 · VCV757890

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	21.2	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 0.102% East Asian · 39/38,236 alleles

Filtering AF 0.0767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0678%

Overall 0.00336% 51/1,516,878 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.102%	980
Remaining individualsnot grpmax-eligible	0.017%	5,889
Admixed American	0.00227%	44,096
European (non-Finnish)	8.8e-05%	1,136,939

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: MSH3
Protein: p.Ala65Pro
Coding: c.193G>C
MANE Select: NM_002439
dbSNP: rs774328125
Type: single nucleotide variant
Location: chr5:80654920 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 65: the 'disordered' region; a UniProt-annotated variant site (sequence variant)

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

Also linked: endometrial carcinoma familial adenomatous polyposis 4

Similar variants

MSH3 p.Ala65Thr Uncertain significance ★★ ⚠ same residue
MSH3 p.Ala65= Likely benign ★★ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>A Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+1G>A Likely pathogenic ★★ same condition
MSH3 c.1653+2T>A 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-ala65pro (accessed [today's date]).

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