Is MSH2 p.Ala2Val (c.5C>T) pathogenic?

MSH2 p.Ala2Val (c.5C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-20). AlphaMissense: likely pathogenic (0.8826); Very rare (popmax 0.00226%, eas); Associated with Muir-Torre syndrome.

What condition is associated with MSH2 p.Ala2Val (c.5C>T)?

MSH2 p.Ala2Val (c.5C>T) is associated with Muir-Torre syndrome, Lynch syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Ala2Val (c.5C>T) in the general population?

MSH2 p.Ala2Val (c.5C>T) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about MSH2 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely pathogenic (score 0.8826) — an in-silico prediction, not a clinical call.

MSH2 p.Ala2Val

c.5C>T · rs587778521 · VCV134840

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.8826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Muir-Torre syndrome

Computational evidence

Protein change
AlphaMissense	0.8826	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -8.43	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 4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	26.4	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 0.00226% East Asian · 1/44,234 alleles

Filtering AF 0.000768% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000609%

Overall 0.001% 16/1,594,834 alleles · very rare exomes 14/1,442,598 · genomes 2/152,236 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,234
European (non-Finnish)	0.00128%	78,140

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: MSH2
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_000251
dbSNP: rs587778521
Type: single nucleotide variant
Location: chr2:47403196 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 2: a UniProt-annotated variant site (in lynch1; likely benign); a modified residue (n-acetylalanine)

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Muir-Torre syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 1 hereditary neoplastic syndrome mismatch repair cancer syndrome 2

Similar variants

MSH2 p.Ala2Thr Likely benign ★★★ ⚠ same residue
MSH2 p.Ala2Glu Uncertain significance ★★ ⚠ same residue
MSH2 p.Ala2= Benign/Likely benign ★★ same residue
MSH2 p.Ala2_Glu7dup Uncertain significance ★★ same residue
MSH2 p.Ala2Ser Uncertain significance ★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C 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/msh2-p-ala2val (accessed [today's date]).

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