Is MSH2 p.Asp459= (c.1377T>C) pathogenic?

MSH2 p.Asp459= (c.1377T>C) is classified Likely benign in MSH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-08-23). Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Asp459= (c.1377T>C)?

MSH2 p.Asp459= (c.1377T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Asp459= (c.1377T>C) in the general population?

MSH2 p.Asp459= (c.1377T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

MSH2 p.Asp459=

c.1377T>C · rs876658353 · VCV230048

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 1.8	GERP 0.51, phastCons 1
Overall
CADD	7.644	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,712 alleles

Overall 6.25e-05% 1/1,599,416 alleles · very rare exomes 1/1,447,064 · genomes 0/152,352 · 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.Asp459=
Coding: c.1377T>C
MANE Select: NM_000251
dbSNP: rs876658353
Type: single nucleotide variant
Location: chr2:47445648 (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

Similar variants

MSH2 p.Asp459Gly Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp459His Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp459Tyr Uncertain significance ★★ ⚠ same residue
MSH2 p.Asp459Ala Uncertain significance ★ ⚠ same residue
MSH2 p.Asp459Glu Uncertain significance ★ ⚠ same residue
MSH2 p.Asp459delinsGluLeuTer Pathogenic ★ same residue
MSH2 p.Asp459Asn Uncertain significance ★ ⚠ 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-asp459 (accessed [today's date]).

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