Is MSH3 p.Pro49fs (c.146del) pathogenic?

MSH3 p.Pro49fs (c.146del) is classified Pathogenic/Likely pathogenic in MSH3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-29). Very rare (popmax 0.00026%, nfe); Associated with endometrial carcinoma.

What condition is associated with MSH3 p.Pro49fs (c.146del)?

MSH3 p.Pro49fs (c.146del) is associated with endometrial carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro49fs (c.146del) in the general population?

MSH3 p.Pro49fs (c.146del) is very rare (popmax 0.00026%, nfe) (gnomAD).

MSH3 p.Pro49fs

c.146del · rs1580538168 · VCV648581

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00026%, nfe)

Conditions

endometrial carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.41	GERP -3.8

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00026% European (non-Finnish) · 3/1,153,958 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00021% 3/1,425,590 alleles · very rare

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.Pro49fs
Coding: c.146del
MANE Select: NM_002439
dbSNP: rs1580538168
Type: Deletion
Location: chr5:80654871 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 49: the 'disordered' region

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

Also linked: hereditary neoplastic syndrome

Similar variants

MSH3 p.Pro49Ala Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro49Thr Uncertain significance ★★ ⚠ same residue
MSH3 c.2253+3_2253+7del Pathogenic/Likely pathogenic ★★ same condition
MSH3 c.2814delG Pathogenic ★★ same condition
MSH3 c.2988_3000+893del Likely pathogenic ★★ same condition
MSH3 p.Ala283fs Pathogenic ★★ same condition
MSH3 p.Ala44fs Pathogenic/Likely pathogenic ★★ same condition
MSH3 p.Arg150fs 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-pro49fs (accessed [today's date]).

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