Is MSH3 p.Pro90Ser (c.268C>T) pathogenic?

MSH3 p.Pro90Ser (c.268C>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-18). AlphaMissense: likely benign (0.0742); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro90Ser (c.268C>T)?

MSH3 p.Pro90Ser (c.268C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro90Ser (c.268C>T) in the general population?

MSH3 p.Pro90Ser (c.268C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MSH3 p.Pro90Ser (c.268C>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

MSH3 p.Pro90Ser

c.268C>T · rs772032731 · VCV1474270

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -1.1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	8.039	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,008 alleles

Overall 0.000124% 2/1,614,040 alleles · very rare exomes 2/1,461,802 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	8.47e-05%	1,179,965

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: MSH3
Protein: p.Pro90Ser
Coding: c.268C>T
MANE Select: NM_002439
dbSNP: rs772032731
Type: single nucleotide variant
Location: chr5:80656441 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 90: the 'disordered' region; the 'interaction with exo1' region

Full MSH3 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

MSH3 p.Pro90Leu Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro90Thr Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro90= Likely benign ★★ same residue
MSH3 p.Pro90Arg Uncertain significance ★ ⚠ same residue
MSH3 p.Pro90Gln Uncertain significance ★ ⚠ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+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/msh3-p-pro90ser (accessed [today's date]).

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