Is MSH2 p.Ser558Pro (c.1672T>C) pathogenic?

MSH2 p.Ser558Pro (c.1672T>C) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-03). AlphaMissense: likely pathogenic (0.841); No allele count reported in gnomAD v4.1 (AN 1,507,604); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Ser558Pro (c.1672T>C)?

MSH2 p.Ser558Pro (c.1672T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser558Pro (c.1672T>C) in the general population?

MSH2 p.Ser558Pro (c.1672T>C) is no allele count reported in gnomAD v4.1 (AN 1,507,604) (gnomAD).

What do computational predictors say about MSH2 p.Ser558Pro (c.1672T>C)?

AlphaMissense predicts likely pathogenic (score 0.841) — an in-silico prediction, not a clinical call.

MSH2 p.Ser558Pro

c.1672T>C · rs1667073007 · VCV1777733

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.841 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,507,604)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.841	likely pathogenic
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -8.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	24.4	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

No allele count reported in gnomAD v4.1 (AN 1,507,604). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MSH2
Protein: p.Ser558Pro
Coding: c.1672T>C
MANE Select: NM_000251
dbSNP: rs1667073007
Type: single nucleotide variant
Location: chr2:47470975 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 558: an α-helix

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH2 p.Ser558Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser558Tyr Uncertain significance ★ ⚠ same residue
MSH2 p.Ser558_Leu559insTer Pathogenic ★★★ same residue
MSH2 p.Ser558_Glu562delinsTer Pathogenic ★ 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-ser558pro (accessed [today's date]).

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