Is MSH6 p.Ala1306Pro (c.3916G>C) pathogenic?

MSH6 p.Ala1306Pro (c.3916G>C) is classified Uncertain significance in MSH6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Ala1306Pro (c.3916G>C)?

MSH6 p.Ala1306Pro (c.3916G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Ala1306Pro (c.3916G>C) in the general population?

MSH6 p.Ala1306Pro (c.3916G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH6 p.Ala1306Pro (c.3916G>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

MSH6 p.Ala1306Pro

c.3916G>C · VCV4657677

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9986 · 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	0.9986	likely pathogenic · top 2% in MSH6
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -17.91	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	27.2	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.Ala1306Pro
Coding: c.3916G>C
MANE Select: NM_000179
Type: single nucleotide variant
Location: chr2:47806566 (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.Ala1306Thr Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala1306Val Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala1306= Benign/Likely benign ★★ same residue
MSH6 p.Ala1306_Asn1307insLeuTer Pathogenic ★ same residue
MSH6 p.Ala1306_Glu1310delinsPheLeuLeuPheLysArgAspIle Uncertain significance ★ same residue
MSH6 p.Ala1306Gly Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A 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-ala1306pro (accessed [today's date]).

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