Is MSH3 p.Pro67Ser (c.199C>T) pathogenic?

MSH3 p.Pro67Ser (c.199C>T) is classified Uncertain significance in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: likely benign (0.0856); Ultra-rare (popmax 0.0174%, afr); Associated with endometrial carcinoma.

What condition is associated with MSH3 p.Pro67Ser (c.199C>T)?

MSH3 p.Pro67Ser (c.199C>T) is associated with endometrial carcinoma, familial adenomatous polyposis 4 (ClinVar).

How common is MSH3 p.Pro67Ser (c.199C>T) in the general population?

MSH3 p.Pro67Ser (c.199C>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about MSH3 p.Pro67Ser (c.199C>T)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

MSH3 p.Pro67Ser

c.199C>T · VCV3592787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

endometrial carcinoma

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.1	GERP -2.7, phastCons 0.59
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	11.99	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

Grpmax group 0.0174% African / African-American · 6/34,508 alleles

Filtering AF 0.00752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00508%

Overall 0.0015% 12/798,688 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,751
Admixed American	0.00409%	24,428
European (non-Finnish)	0.000849%	117,793

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.Pro67Ser
Coding: c.199C>T
MANE Select: NM_000791 · reported on NM_002439
Type: single nucleotide variant
Location: chr5:80654926 (GRCh38)

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

Disease context

endometrial carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 4

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-pro67ser (accessed [today's date]).

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