Is MSH6 p.Ser256= (c.768T>C) pathogenic?

MSH6 p.Ser256= (c.768T>C) is classified Likely benign in MSH6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-05). Very rare (popmax 8.48e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Ser256= (c.768T>C)?

MSH6 p.Ser256= (c.768T>C) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH6 p.Ser256= (c.768T>C) in the general population?

MSH6 p.Ser256= (c.768T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

MSH6 p.Ser256=

c.768T>C · rs1558659235 · VCV633315

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 -0.45, phastCons 0.073
Overall
CADD	8.232	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,936 alleles

Overall 6.2e-05% 1/1,613,682 alleles · very rare exomes 1/1,461,886 · genomes 0/151,796 · 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.Ser256=
Coding: c.768T>C
MANE Select: NM_000179
dbSNP: rs1558659235
Type: single nucleotide variant
Location: chr2:47798751 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 256: a modified residue (phosphoserine); the 'disordered' region

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

Similar variants

MSH6 p.Ser256fs Pathogenic ★★ same residue
MSH6 p.Ser256Asn Uncertain significance ★★ ⚠ same residue
MSH6 p.Ser256Cys Uncertain significance ★ ⚠ same residue
MSH6 c.3173-3C>G Pathogenic/Likely pathogenic ★★ same condition
MSH6 c.3557-1G>A Likely pathogenic ★★ same condition
MSH6 c.3557-1G>C Pathogenic/Likely pathogenic ★★ same condition
MSH6 c.3557-1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH6 c.3646+1G>A Pathogenic/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-ser256 (accessed [today's date]).

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