Is MSH3 p.Asp705= (c.2115C>T) pathogenic?

MSH3 p.Asp705= (c.2115C>T) is classified Conflicting classifications of pathogenicity in MSH3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-30). Very rare (popmax 0.00246%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Asp705= (c.2115C>T)?

MSH3 p.Asp705= (c.2115C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Asp705= (c.2115C>T) in the general population?

MSH3 p.Asp705= (c.2115C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

MSH3 p.Asp705=

c.2115C>T · rs575812929 · VCV760379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.091	GERP 0.024, phastCons 0.92
Overall
CADD	11.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,177,218 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.0018% 29/1,610,452 alleles · very rare

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: MSH3
Protein: p.Asp705=
Coding: c.2115C>T
MANE Select: NM_002439
dbSNP: rs575812929
Type: single nucleotide variant
Location: chr5:80768865 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB

Full MSH3 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

MSH3 p.Asp705Gly Uncertain significance ★★ ⚠ same residue
MSH3 p.Asp705Tyr Uncertain significance ★ ⚠ same residue
MSH3 p.Asp705His Uncertain significance ★ ⚠ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+1G>A Likely pathogenic ★★ same condition
MSH3 c.1764-1G>A 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/msh3-p-asp705 (accessed [today's date]).

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