Is MSH2 p.Ala70= (c.210A>C) pathogenic?

MSH2 p.Ala70= (c.210A>C) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). Very rare (popmax 0.00267%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ala70= (c.210A>C)?

MSH2 p.Ala70= (c.210A>C) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH2 p.Ala70= (c.210A>C) in the general population?

MSH2 p.Ala70= (c.210A>C) is very rare (popmax 0.00267%, afr) (gnomAD).

MSH2 p.Ala70=

c.210A>C · rs1230662279 · VCV525735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.53	donor gain · deltas
Pangolin	Δ0.30	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -0.88, phastCons 1
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,850 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000125% 2/1,597,284 alleles · very rare exomes 2/1,444,940 · genomes 0/152,344 · 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.Ala70=
Coding: c.210A>C
MANE Select: NM_000251
dbSNP: rs1230662279
Type: single nucleotide variant
Location: chr2:47403401 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 70: 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.Ala70Ser Uncertain significance ★ ⚠ same residue
MSH2 p.Ala70Val Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ala70Thr 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-ala70 (accessed [today's date]).

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