Is MSH6 p.Ala780Pro (c.2338G>C) pathogenic?

MSH6 p.Ala780Pro (c.2338G>C) is classified Uncertain significance in MSH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.9252); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Ala780Pro (c.2338G>C)?

MSH6 p.Ala780Pro (c.2338G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Ala780Pro (c.2338G>C) in the general population?

MSH6 p.Ala780Pro (c.2338G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH6 p.Ala780Pro (c.2338G>C)?

AlphaMissense predicts likely pathogenic (score 0.9252) — an in-silico prediction, not a clinical call.

MSH6 p.Ala780Pro

c.2338G>C · VCV3875092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9252 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9252	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -12.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: MSH6
Protein: p.Ala780Pro
Coding: c.2338G>C
MANE Select: NM_000179
Type: single nucleotide variant
Location: chr2:47800321 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB

Full MSH6 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

MSH6 p.Ala780= Benign/Likely benign ★★ same residue
MSH6 p.Ala780Asp Uncertain significance ★ ⚠ same residue
MSH6 p.Ala780Val Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ala780fs Pathogenic ★★ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>T Likely pathogenic ★★★ same condition
MSH6 c.3439-2A>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/msh6-p-ala780pro (accessed [today's date]).

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