Is MSH3 p.Pro681Ser (c.2041C>T) pathogenic?

MSH3 p.Pro681Ser (c.2041C>T) is classified Conflicting classifications of pathogenicity in MSH3 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-04-15). AlphaMissense: likely benign (0.1116); Rare (popmax 0.229%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro681Ser (c.2041C>T)?

MSH3 p.Pro681Ser (c.2041C>T) is associated with hereditary neoplastic syndrome, endometrial carcinoma, familial adenomatous polyposis 4 (ClinVar).

How common is MSH3 p.Pro681Ser (c.2041C>T) in the general population?

MSH3 p.Pro681Ser (c.2041C>T) is rare (popmax 0.229%, nfe) (gnomAD).

What do computational predictors say about MSH3 p.Pro681Ser (c.2041C>T)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

MSH3 p.Pro681Ser

c.2041C>T · rs115198722 · VCV656200

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.229%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -6.89	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 1.8	GERP 1.3, phastCons 0.93
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	20.8	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 0.229% European (non-Finnish) · 2,699/1,179,722 alleles

Filtering AF 0.222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.219%

Overall 0.174% 2,814/1,613,708 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.229%	437
Amishnot grpmax-eligible	0.11%	912
Remaining individualsnot grpmax-eligible	0.088%	1,136
African / African-American	0.036%	2,778
Admixed American	0.03%	3,334
Finnishnot grpmax-eligible	0.0156%	6,402
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,398

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.Pro681Ser
Coding: c.2041C>T
MANE Select: NM_002439
dbSNP: rs115198722
Type: single nucleotide variant
Location: chr5:80768077 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 681: a turn

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.Pro681= Likely benign ★★ same residue
MSH3 p.Pro681Thr 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>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-pro681ser (accessed [today's date]).

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