Is MSH3 p.Ser2Pro (c.4T>C) pathogenic?

MSH3 p.Ser2Pro (c.4T>C) is classified Likely benign in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-12). AlphaMissense: likely benign (0.0781); Very rare (popmax 0.00111%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Ser2Pro (c.4T>C)?

MSH3 p.Ser2Pro (c.4T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Ser2Pro (c.4T>C) in the general population?

MSH3 p.Ser2Pro (c.4T>C) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about MSH3 p.Ser2Pro (c.4T>C)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

MSH3 p.Ser2Pro

c.4T>C · VCV4860361

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

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	0.0781	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.23	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	GERP -3.7
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	11.04	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 0.00111% South Asian · 1/90,208 alleles

Overall 6.25e-05% 1/1,599,342 alleles · very rare exomes 1/1,447,362 · genomes 0/151,980 · 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.Ser2Pro
Coding: c.4T>C
MANE Select: NM_002439
Type: single nucleotide variant
Location: chr5:80654731 (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-ser2pro (accessed [today's date]).

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