Is MSH2 p.Asp461= (c.1383T>C) pathogenic?

MSH2 p.Asp461= (c.1383T>C) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-09). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Asp461= (c.1383T>C)?

MSH2 p.Asp461= (c.1383T>C) is associated with hereditary neoplastic syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Asp461= (c.1383T>C) in the general population?

MSH2 p.Asp461= (c.1383T>C) is absent from gnomAD v4.1 (gnomAD).

MSH2 p.Asp461=

c.1383T>C · rs1114167881 · VCV428557

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -3.5, phastCons 1
Overall
CADD	5.615	PHRED · no single calibrated threshold — expert panels disagree

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.Asp461=
Coding: c.1383T>C
MANE Select: NM_000251
dbSNP: rs1114167881
Type: single nucleotide variant
Location: chr2:47445654 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

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.Asp461Gly Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp461Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Asp461Glu Uncertain significance ★ ⚠ same residue
MSH2 p.Asp461fs Pathogenic ★ same residue
MSH2 p.Asp461His Uncertain significance ★ ⚠ same residue
MSH2 p.Asp461Tyr Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+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/msh2-p-asp461 (accessed [today's date]).

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