Is MSH3 p.Pro783Ser (c.2347C>T) pathogenic?

MSH3 p.Pro783Ser (c.2347C>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.2447); Very rare (popmax 0.00439%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro783Ser (c.2347C>T)?

MSH3 p.Pro783Ser (c.2347C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro783Ser (c.2347C>T) in the general population?

MSH3 p.Pro783Ser (c.2347C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about MSH3 p.Pro783Ser (c.2347C>T)?

AlphaMissense predicts likely benign (score 0.2447) — an in-silico prediction, not a clinical call.

MSH3 p.Pro783Ser

c.2347C>T · rs778848549 · VCV1789938

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2447 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2447	likely benign
REVEL	0.74	pathogenic-leaning
SaProt	LLR -10.17	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	27.7	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 0.00439% South Asian · 4/91,028 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000479% 7/1,459,946 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,757
Remaining individualsnot grpmax-eligible	0.0016%	62,450
Finnishnot grpmax-eligible	0.00156%	64,018
African / African-American	0.00133%	75,016

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.Pro783Ser
Coding: c.2347C>T
MANE Select: NM_002439
dbSNP: rs778848549
Type: single nucleotide variant
Location: chr5:80778748 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 783: an α-helix

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

Similar variants

MSH3 p.Pro783Ala Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro783His Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro783Leu Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro783Thr Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro783= Likely benign ★ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C 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-pro783ser (accessed [today's date]).

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