Is MSH2 p.Val273= (c.819A>G) pathogenic?

MSH2 p.Val273= (c.819A>G) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-06-01). Rare (popmax 0.291%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Val273= (c.819A>G)?

MSH2 p.Val273= (c.819A>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, Muir-Torre syndrome (ClinVar).

How common is MSH2 p.Val273= (c.819A>G) in the general population?

MSH2 p.Val273= (c.819A>G) is rare (popmax 0.291%, afr) (gnomAD).

MSH2 p.Val273=

c.819A>G · rs146577635 · VCV135864

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

rare (popmax 0.291%, afr)

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 -0.069	GERP -3.1, phastCons 0.028
Overall
CADD	2.763	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.291% African / African-American · 218/74,966 alleles

Filtering AF 0.259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.247%

Overall 0.0156% 252/1,613,260 alleles · rare exomes 112/1,461,154 · genomes 140/152,106 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.291%	344
Admixed American	0.0351%	2,851
Remaining individualsnot grpmax-eligible	0.016%	6,248
South Asian	0.0033%	30,267

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.Val273=
Coding: c.819A>G
MANE Select: NM_000251
dbSNP: rs146577635
Type: single nucleotide variant
Location: chr2:47414295 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 273: an α-helix; a UniProt-annotated variant site (in lynch1)

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 mismatch repair cancer syndrome 2

Similar variants

MSH2 p.Val273Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Val273Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Val273Leu 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
MSH2 c.1077-2A>C 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-val273 (accessed [today's date]).

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