Is MSH6 p.Ala23Ser (c.67G>T) pathogenic?

MSH6 p.Ala23Ser (c.67G>T) is classified Conflicting classifications of pathogenicity in MSH6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.0785); Very rare (popmax 8.48e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH6 p.Ala23Ser (c.67G>T) in the general population?

MSH6 p.Ala23Ser (c.67G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MSH6 p.Ala23Ser (c.67G>T)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

MSH6 p.Ala23Ser

Q: What condition is associated with MSH6 p.Ala23Ser (c.67G>T)?

MSH6 p.Ala23Ser (c.67G>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.67G>T · rs730881810 · VCV1023383

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -1.1, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	11.26	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 8.48e-05% European (non-Finnish) · 1/1,179,548 alleles

Overall 6.2e-05% 1/1,612,090 alleles · very rare exomes 1/1,459,784 · genomes 0/152,306 · 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.Ala23Ser
Coding: c.67G>T
MANE Select: NM_000179
dbSNP: rs730881810
Type: single nucleotide variant
Location: chr2:47783300 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 23: 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

Also linked: hereditary neoplastic syndrome

Similar variants

MSH6 p.Ala23Asp Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala23Gly Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala23Val Uncertain significance ★★ ⚠ same residue
MSH6 p.Ala23= Benign/Likely benign ★★ same residue
MSH6 p.Ala23Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ala23Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ala23fs Pathogenic ★ same residue
MSH6 c.3172+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-ala23ser (accessed [today's date]).

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