Is MSH6 p.Pro656= (c.1968C>A) pathogenic?

MSH6 p.Pro656= (c.1968C>A) is classified Likely benign in MSH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-18). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Pro656= (c.1968C>A)?

MSH6 p.Pro656= (c.1968C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Pro656= (c.1968C>A) in the general population?

MSH6 p.Pro656= (c.1968C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MSH6 p.Pro656=

c.1968C>A · rs1553413333 · VCV1783551

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	GERP -1.1
Overall
CADD	3.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.2e-05% 1/1,614,014 alleles · very rare exomes 1/1,461,886 · genomes 0/152,128 · joint denominator

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: MSH6
Protein: p.Pro656=
Coding: c.1968C>A
MANE Select: NM_000179
dbSNP: rs1553413333
Type: single nucleotide variant
Location: chr2:47799951 (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.Pro656Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro656Ala Uncertain significance ★ ⚠ same residue
MSH6 p.Pro656His Uncertain significance ★ ⚠ same residue
MSH6 p.Pro656Ser Uncertain significance ★ ⚠ same residue
MSH6 p.Pro656Arg Uncertain significance ★ ⚠ 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

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-pro656 (accessed [today's date]).

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