Is MSH2 p.Ser13Arg (c.39C>A) pathogenic?

MSH2 p.Ser13Arg (c.39C>A) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.721); Very rare (popmax 0.00034%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser13Arg (c.39C>A)?

MSH2 p.Ser13Arg (c.39C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser13Arg (c.39C>A) in the general population?

MSH2 p.Ser13Arg (c.39C>A) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Ser13Arg (c.39C>A)?

AlphaMissense predicts likely pathogenic (score 0.721) — an in-silico prediction, not a clinical call.

MSH2 p.Ser13Arg

c.39C>A · rs1060502015 · VCV408509

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.721	likely pathogenic
REVEL	0.603	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.91, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	20.6	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

Grpmax group 0.00034% European (non-Finnish) · 4/1,174,882 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00025% 4/1,600,284 alleles · very rare exomes 4/1,447,912 · genomes 0/152,372 · 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.Ser13Arg
Coding: c.39C>A
MANE Select: NM_000251
dbSNP: rs1060502015
Type: single nucleotide variant
Location: chr2:47403230 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 13: a UniProt-annotated variant site (in crc; uncertain significance)

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 hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser13Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser13Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser13= Likely benign ★ 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-ser13arg (accessed [today's date]).

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