Is MSH3 p.Pro49Ser (c.145C>T) pathogenic?

MSH3 p.Pro49Ser (c.145C>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.0697); Very rare (popmax 0.00891%, nfe); Associated with MSH3-related disorder.

What condition is associated with MSH3 p.Pro49Ser (c.145C>T)?

MSH3 p.Pro49Ser (c.145C>T) is associated with MSH3-related disorder, endometrial carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro49Ser (c.145C>T) in the general population?

MSH3 p.Pro49Ser (c.145C>T) is very rare (popmax 0.00891%, nfe) (gnomAD).

What do computational predictors say about MSH3 p.Pro49Ser (c.145C>T)?

AlphaMissense predicts likely benign (score 0.0697) — an in-silico prediction, not a clinical call.

MSH3 p.Pro49Ser

c.145C>T · rs775307118 · VCV651887

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MSH3-related disorder

⚠ 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	0.0697	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -5.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.34	GERP -0.026
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	5.752	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 0.00891% European (non-Finnish) · 102/1,144,620 alleles

Filtering AF 0.00747% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00697%

Overall 0.00672% 105/1,561,422 alleles · very rare exomes 102/1,416,568 · genomes 3/144,854 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00891%	11,222
African / African-American	0.0029%	34,451
South Asian	0.00112%	89,660

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.Pro49Ser
Coding: c.145C>T
MANE Select: NM_002439
dbSNP: rs775307118
Type: single nucleotide variant
Location: chr5:80654872 (GRCh38)

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

Disease context

MSH3-related disorder

Also linked: endometrial carcinoma hereditary neoplastic syndrome 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-pro49ser (accessed [today's date]).

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