Is MSH2 p.Ser928Pro (c.2782T>C) pathogenic?

MSH2 p.Ser928Pro (c.2782T>C) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-03-04). AlphaMissense: ambiguous (0.3962); Very rare (popmax 0.00017%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser928Pro (c.2782T>C)?

MSH2 p.Ser928Pro (c.2782T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser928Pro (c.2782T>C) in the general population?

MSH2 p.Ser928Pro (c.2782T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Ser928Pro (c.2782T>C)?

AlphaMissense predicts ambiguous (score 0.3962) — an in-silico prediction, not a clinical call.

MSH2 p.Ser928Pro

c.2782T>C · rs587781852 · VCV219489

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.3962	ambiguous
REVEL	0.683	pathogenic-leaning
SaProt	LLR -8.58	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.72, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	22.1	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 0.00017% European (non-Finnish) · 2/1,179,380 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,036 alleles · very rare exomes 2/1,459,718 · genomes 0/152,318 · 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.Ser928Pro
Coding: c.2782T>C
MANE Select: NM_000251
dbSNP: rs587781852
Type: single nucleotide variant
Location: chr2:47482926 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 928: 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: hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser928Ala Uncertain significance ★★ ⚠ same residue
MSH2 p.Ser928= Benign/Likely benign ★★ same residue
MSH2 p.Ser928Leu Likely benign ★ same residue
MSH2 p.Ser928fs Uncertain significance ★ same residue
MSH2 p.Ser928Ter 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

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-ser928pro (accessed [today's date]).

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