Is MSH2 p.Val17Ile (c.49G>A) pathogenic?

MSH2 p.Val17Ile (c.49G>A) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-05). AlphaMissense: likely benign (0.0841); Very rare (popmax 8.51e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Val17Ile (c.49G>A)?

MSH2 p.Val17Ile (c.49G>A) is associated with hereditary neoplastic syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Val17Ile (c.49G>A) in the general population?

MSH2 p.Val17Ile (c.49G>A) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Val17Ile (c.49G>A)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

MSH2 p.Val17Ile

c.49G>A · rs63750966 · VCV491829

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -3.98	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 1.1	GERP -5.1, phastCons 0.56
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	13.0	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 8.51e-05% European (non-Finnish) · 1/1,174,666 alleles

Overall 6.25e-05% 1/1,599,550 alleles · very rare exomes 0/1,447,282 · genomes 1/152,268 · 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: MSH2
Protein: p.Val17Ile
Coding: c.49G>A
MANE Select: NM_000251
dbSNP: rs63750966
Type: single nucleotide variant
Location: chr2:47403240 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 17: an α-helix; a UniProt-annotated variant site (in gastric cancer; uncertain significance; cryptic acceptor splice site suppressed on ex vivo splicing assay)

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

Disease context

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

Also linked: Lynch syndrome 1

Similar variants

MSH2 p.Val17= Benign/Likely benign ★★ same residue
MSH2 p.Val17Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Val17Phe Conflicting classifications of pathogenicity ★ ⚠ 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
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C 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-val17ile (accessed [today's date]).

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