Is MSH6 p.Trp970Arg (c.2908T>C) pathogenic?

MSH6 p.Trp970Arg (c.2908T>C) is classified Uncertain significance in MSH6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-20). AlphaMissense: likely pathogenic (0.9338); Very rare (popmax 0.00134%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Trp970Arg (c.2908T>C)?

MSH6 p.Trp970Arg (c.2908T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Trp970Arg (c.2908T>C) in the general population?

MSH6 p.Trp970Arg (c.2908T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MSH6 p.Trp970Arg (c.2908T>C)?

AlphaMissense predicts likely pathogenic (score 0.9338) — an in-silico prediction, not a clinical call.

MSH6 p.Trp970Arg

c.2908T>C · rs1410870321 · VCV941629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9338 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.9338	likely pathogenic
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,396 alleles

Overall 0.000125% 2/1,605,240 alleles · very rare exomes 1/1,453,076 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,396
European (non-Finnish)	8.5e-05%	1,176,158

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.Trp970Arg
Coding: c.2908T>C
MANE Select: NM_000179
dbSNP: rs1410870321
Type: single nucleotide variant
Location: chr2:47800891 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 970: 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: hereditary neoplastic syndrome

Similar variants

MSH6 p.Trp970Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Trp970Leu Uncertain significance ★ ⚠ same residue
MSH6 p.Trp970Ter Pathogenic/Likely 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
MSH6 c.3647-1G>A 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-trp970arg (accessed [today's date]).

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