Is MSH6 p.Val424= (c.1272C>T) pathogenic?

MSH6 p.Val424= (c.1272C>T) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-25). Very rare (popmax 0.00133%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH6 p.Val424= (c.1272C>T) in the general population?

MSH6 p.Val424= (c.1272C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

MSH6 p.Val424=

Q: What condition is associated with MSH6 p.Val424= (c.1272C>T)?

MSH6 p.Val424= (c.1272C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 5 (ClinVar).

c.1272C>T · rs63751452 · VCV416140

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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 0.02	GERP -1.9, phastCons 0.81
Overall
CADD	4.422	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,024 alleles

Overall 6.2e-05% 1/1,614,054 alleles · very rare exomes 1/1,461,808 · genomes 0/152,246 · 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.Val424=
Coding: c.1272C>T
MANE Select: NM_000179
dbSNP: rs63751452
Type: single nucleotide variant
Location: chr2:47799255 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 424: a β-strand

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 Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Val424Ala Uncertain significance ★★ ⚠ same residue
MSH6 p.Val424Ile Uncertain significance ★★ ⚠ same residue
MSH6 p.Val424Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Val424fs Pathogenic ★ 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-val424 (accessed [today's date]).

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