Is MSH2 p.Ser494Pro (c.1480T>C) pathogenic?

MSH2 p.Ser494Pro (c.1480T>C) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-28). AlphaMissense: likely pathogenic (0.769); Ultra-rare (popmax 0.0178%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Ser494Pro (c.1480T>C)?

MSH2 p.Ser494Pro (c.1480T>C) is associated with hereditary neoplastic syndrome, Lynch syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Ser494Pro (c.1480T>C) in the general population?

MSH2 p.Ser494Pro (c.1480T>C) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about MSH2 p.Ser494Pro (c.1480T>C)?

AlphaMissense predicts likely pathogenic (score 0.769) — an in-silico prediction, not a clinical call.

MSH2 p.Ser494Pro

c.1480T>C · rs55653533 · VCV233001

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.769	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -11.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP 0.72, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	22.9	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 0.0178% East Asian · 8/44,834 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00062% 10/1,613,976 alleles · ultra-rare exomes 9/1,461,702 · genomes 1/152,274 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,604
Remaining individualsnot grpmax-eligible	0.0032%	31,249

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.Ser494Pro
Coding: c.1480T>C
MANE Select: NM_000251
dbSNP: rs55653533
Type: single nucleotide variant
Location: chr2:47463124 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 494: an α-helix

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 Lynch syndrome 1 Muir-Torre syndrome hereditary nonpolyposis colon cancer mismatch repair cancer syndrome 2

Similar variants

MSH2 p.Ser494Ter Pathogenic ★ same residue
MSH2 p.Ser494= Benign ★ 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
MSH2 c.1077-2A>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/msh2-p-ser494pro (accessed [today's date]).

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