Is MSH2 p.Ser540Arg (c.1620T>A) pathogenic?

MSH2 p.Ser540Arg (c.1620T>A) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-07). AlphaMissense: ambiguous (0.399); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser540Arg (c.1620T>A)?

MSH2 p.Ser540Arg (c.1620T>A) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH2 p.Ser540Arg (c.1620T>A) in the general population?

MSH2 p.Ser540Arg (c.1620T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Ser540Arg (c.1620T>A)?

AlphaMissense predicts ambiguous (score 0.399) — an in-silico prediction, not a clinical call.

MSH2 p.Ser540Arg

c.1620T>A · rs1057521172 · VCV2134938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.399 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.399	ambiguous
REVEL	0.433	indeterminate
SaProt	LLR -5.30	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP -0.3, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	16.69	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH2
Protein: p.Ser540Arg
Coding: c.1620T>A
MANE Select: NM_000251
dbSNP: rs1057521172
Type: single nucleotide variant
Location: chr2:47466767 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 540: a β-strand

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.Ser540Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser540fs Pathogenic ★★ same residue
MSH2 p.Ser540= Likely benign ★★ same residue
MSH2 p.Ser540Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser540Thr 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

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-ser540arg (accessed [today's date]).

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