Is MSH2 p.Arg359Ser (c.1077A>T) pathogenic?

MSH2 p.Arg359Ser (c.1077A>T) is classified Pathogenic in MSH2 (ClinVar, Expert panel, 3 submitters; last evaluated 2013-09-05). AlphaMissense: likely pathogenic (0.9945); Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MSH2 p.Arg359Ser (c.1077A>T)?

MSH2 p.Arg359Ser (c.1077A>T) is associated with Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Arg359Ser (c.1077A>T) in the general population?

MSH2 p.Arg359Ser (c.1077A>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH2 p.Arg359Ser (c.1077A>T)?

AlphaMissense predicts likely pathogenic (score 0.9945) — an in-silico prediction, not a clinical call.

MSH2 p.Arg359Ser

c.1077A>T · rs63751617 · VCV90539

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9945 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.9945	likely pathogenic ✓ concordant with ClinVar · top 6% in MSH2
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -15.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.42	GERP -0.59, phastCons 0.77
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	22.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH2
Protein: p.Arg359Ser
Coding: c.1077A>T
MANE Select: NM_000251
dbSNP: rs63751617
Type: single nucleotide variant
Location: chr2:47429742 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 359: an α-helix; a UniProt-annotated variant site (in lynch1; shows a decreased expression level of the muts alpha complex; associated with an abnormal subcellular localization pattern)

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

Disease context

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

Also linked: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Arg359Ter Pathogenic ★★★ same residue
MSH2 p.Arg359Gly Likely pathogenic ★★ same residue
MSH2 p.Arg359Ile Likely pathogenic ★★ same residue
MSH2 p.Arg359Thr Pathogenic/Likely pathogenic ★★ same residue
MSH2 p.Arg359Lys Uncertain significance ★★ ⚠ same residue
MSH2 p.Arg359fs Pathogenic ★ same residue
MSH2 p.Arg359= Benign ★ same residue
MSH2 c.1076+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/msh2-p-arg359ser (accessed [today's date]).

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