Is MSH2 p.Ala72= (c.216A>G) pathogenic?

MSH2 p.Ala72= (c.216A>G) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-11). Ultra-rare (popmax 0.0562%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ala72= (c.216A>G)?

MSH2 p.Ala72= (c.216A>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, Muir-Torre syndrome (ClinVar).

How common is MSH2 p.Ala72= (c.216A>G) in the general population?

MSH2 p.Ala72= (c.216A>G) is ultra-rare (popmax 0.0562%, sas) (gnomAD).

MSH2 p.Ala72=

c.216A>G · rs746298214 · VCV491797

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0562%, sas)

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 1.1	GERP -1.1, phastCons 0.99
Overall
CADD	9.513	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0562% South Asian · 51/90,750 alleles

Filtering AF 0.0438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.00329% 53/1,611,384 alleles · ultra-rare exomes 52/1,459,290 · genomes 1/152,094 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0562%	1,779
Remaining individualsnot grpmax-eligible	0.00321%	31,199

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.Ala72=
Coding: c.216A>G
MANE Select: NM_000251
dbSNP: rs746298214
Type: single nucleotide variant
Location: chr2:47408405 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 72: 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

Also linked: Lynch syndrome 1 Muir-Torre syndrome hereditary neoplastic syndrome

Similar variants

MSH2 p.Ala72Gly Uncertain significance ★★ ⚠ same residue
MSH2 p.Ala72Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ala72Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ala72Glu Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>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-ala72 (accessed [today's date]).

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