Is MSH6 p.Pro408= (c.1224T>G) pathogenic?

MSH6 p.Pro408= (c.1224T>G) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-17). Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Pro408= (c.1224T>G)?

MSH6 p.Pro408= (c.1224T>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Pro408= (c.1224T>G) in the general population?

MSH6 p.Pro408= (c.1224T>G) is absent from gnomAD v4.1 (gnomAD).

MSH6 p.Pro408=

c.1224T>G · rs786203834 · VCV187573

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.2	GERP 0.88, phastCons 0.98
Overall
CADD	6.919	PHRED · no single calibrated threshold — expert panels disagree

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.Pro408=
Coding: c.1224T>G
MANE Select: NM_000179
dbSNP: rs786203834
Type: single nucleotide variant
Location: chr2:47799207 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 408: an α-helix

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Pro408Arg Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro408Ser Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro408Thr Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro408Ala Uncertain significance ★ ⚠ same residue
MSH6 p.Pro408His Uncertain significance ★ ⚠ same residue
MSH6 p.Pro408fs Pathogenic ★ 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-pro408 (accessed [today's date]).

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