Is MSH3 p.Pro18Leu (c.53C>T) pathogenic?

MSH3 p.Pro18Leu (c.53C>T) is classified Uncertain significance in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-12). AlphaMissense: likely benign (0.1574); Absent from gnomAD v4.1; Associated with endometrial carcinoma.

What condition is associated with MSH3 p.Pro18Leu (c.53C>T)?

MSH3 p.Pro18Leu (c.53C>T) is associated with endometrial carcinoma (ClinVar).

How common is MSH3 p.Pro18Leu (c.53C>T) in the general population?

MSH3 p.Pro18Leu (c.53C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH3 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1574) — an in-silico prediction, not a clinical call.

MSH3 p.Pro18Leu

c.53C>T · rs1749189883 · VCV2676764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1574 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

endometrial carcinoma

⚠ 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	0.1574	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.93	GERP -0.94
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	17.38	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH3
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_002439
dbSNP: rs1749189883
Type: single nucleotide variant
Location: chr5:80654780 (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

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-pro18leu (accessed [today's date]).

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