Is MSH3 p.Pro765fs (c.2293_2294insT) pathogenic?

MSH3 p.Pro765fs (c.22932294insT) is classified Pathogenic in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-30). Very rare (popmax 8.64e-05%, nfe); Associated with familial adenomatous polyposis 4.

What condition is associated with MSH3 p.Pro765fs (c.2293_2294insT)?

MSH3 p.Pro765fs (c.2293_2294insT) is associated with familial adenomatous polyposis 4 (ClinVar).

How common is MSH3 p.Pro765fs (c.2293_2294insT) in the general population?

MSH3 p.Pro765fs (c.2293_2294insT) is very rare (popmax 8.64e-05%, nfe) (gnomAD).

How is MSH3-related polyposis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MSH3 p.Pro765fs

c.2293_2294insT · rs1744286516 · VCV2673542

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.64e-05%, nfe)

Conditions

familial adenomatous polyposis 4

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 16 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.64e-05% European (non-Finnish) · 1/1,157,040 alleles

Overall 0.000658% 1/151,944 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.Pro765fs
Coding: c.2293_2294insT
MANE Select: NM_002439
dbSNP: rs1744286516
Type: Insertion
Location: chr5:80775733 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB

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

Disease context

familial adenomatous polyposis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MSH3-related polyposis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

MSH3 p.Glu437fs Pathogenic/Likely pathogenic ★★ same condition
MSH3 p.Ser490fs Pathogenic ★★ same condition
MSH3 p.Pro765Ser Uncertain significance ★★ ⚠ same residue
MSH3 c.2253_2253+1insAT Likely pathogenic ★ same condition
MSH3 p.Ser570fs Pathogenic ★ same condition
MSH3 p.Pro765Arg Uncertain significance ★ ⚠ same residue
MSH3 p.Pro765Thr Uncertain significance ★ ⚠ same residue
MSH3 c.1341-2A>G Likely 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-pro765fs (accessed [today's date]).

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