Is MSH6 p.Val129= (c.387T>G) pathogenic?

MSH6 p.Val129= (c.387T>G) is classified Benign in MSH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-18). Absent from gnomAD v4.1; Associated with Lynch syndrome 5.

What condition is associated with MSH6 p.Val129= (c.387T>G)?

MSH6 p.Val129= (c.387T>G) is associated with Lynch syndrome 5 (ClinVar).

How common is MSH6 p.Val129= (c.387T>G) in the general population?

MSH6 p.Val129= (c.387T>G) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

MSH6 p.Val129=

c.387T>G · VCV3904272

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Lynch syndrome 5

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 0.62	GERP -0.99, phastCons 1
Overall
CADD	6.972	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.Val129=
Coding: c.387T>G
MANE Select: NM_000179
Type: single nucleotide variant
Location: chr2:47791053 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 129: the pwwp domain; a β-strand

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

Disease context

Lynch syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH6 p.Val129Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Val129Phe Uncertain significance ★★ ⚠ same residue
MSH6 p.Val129Ala Uncertain significance ★ ⚠ same residue
MSH6 p.Val129Ile Conflicting classifications of pathogenicity ★ ⚠ 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-val129 (accessed [today's date]).

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