Is MSH2 p.Thr682= (c.2046T>A) pathogenic?

MSH2 p.Thr682= (c.2046T>A) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-18). Very rare (popmax 0.000169%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Thr682= (c.2046T>A)?

MSH2 p.Thr682= (c.2046T>A) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH2 p.Thr682= (c.2046T>A) in the general population?

MSH2 p.Thr682= (c.2046T>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

MSH2 p.Thr682=

c.2046T>A · rs2104370344 · VCV1337426

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 -2.8	GERP -4.1
Overall
CADD	1.773	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,196 alleles · very rare exomes 2/1,461,884 · genomes 0/152,312 · 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.Thr682=
Coding: c.2046T>A
MANE Select: NM_000251
dbSNP: rs2104370344
Type: single nucleotide variant
Location: chr2:47476407 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 682: an α-helix

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH2 p.Thr682Pro Uncertain significance ★ ⚠ same residue
MSH2 p.Thr682Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Thr682Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 c.1276+2T>C Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1277-1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1510+1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1510+2T>C Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1661+2T>C Pathogenic/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-thr682 (accessed [today's date]).

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