Is MSH3 p.Pro76Ser (c.226C>T) pathogenic?

MSH3 p.Pro76Ser (c.226C>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0721); Very rare (popmax 0.000179%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro76Ser (c.226C>T)?

MSH3 p.Pro76Ser (c.226C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro76Ser (c.226C>T) in the general population?

MSH3 p.Pro76Ser (c.226C>T) is very rare (popmax 0.000179%, nfe) (gnomAD).

What do computational predictors say about MSH3 p.Pro76Ser (c.226C>T)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

MSH3 p.Pro76Ser

c.226C>T · rs1261331525 · VCV957679

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.69	GERP -0.46, phastCons 0.001
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	10.79	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 0.000179% European (non-Finnish) · 2/1,115,358 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000135% 2/1,479,468 alleles · very rare exomes 2/1,328,492 · genomes 0/150,976 · 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: MSH3
Protein: p.Pro76Ser
Coding: c.226C>T
MANE Select: NM_002439
dbSNP: rs1261331525
Type: single nucleotide variant
Location: chr5:80654953 (GRCh38)

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

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-pro76ser (accessed [today's date]).

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