TOP2B p.Ala490=
c.1470T>A · rs373737261 · VCV1934353
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0665%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1 | GERP -4.4 |
| Overall | ||
| CADD | 7.474 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0665%
Middle Eastern · 4/6,014 alleles
Filtering AF
0.0227%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0136%
Overall
0.000837%
13/1,552,318 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0665% | 1,503 |
| Remaining individualsnot grpmax-eligible | 0.00332% | 30,103 |
| European (non-Finnish) | 0.00061% | 163,875 |
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
- TOP2B
- Protein
- p.Ala490=
- Coding
- c.1470T>A
- MANE Select
- NM_001330700
- dbSNP
- rs373737261
- Type
- single nucleotide variant
- Location
- chr3:25630405 (GRCh38)
- Gene constraint
- LOEUF 0.328 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 74.09 · 21 PDB
- Residue 490
- a UniProt-annotated variant site (in bilu; decreased protein abundance; severely decreased dna topoisomerase type ii (double strand cut, atp-hydrolyzing) activity); an α-helix; the toprim domain
Similar variants
- TOP2B p.Ala490Pro Pathogenic ★ same residue
- TOP2B p.Ala1290Thr Uncertain significance ★★ ⚠ same type
- TOP2B p.Ala188Gly Uncertain significance ★★ ⚠ same type
- TOP2B p.Ala777Ser Uncertain significance ★★ ⚠ same type
- TOP2B p.Ala890Ser Uncertain significance ★★ ⚠ same type
- TOP2B p.Arg1047Gln Uncertain significance ★★ ⚠ same type
- TOP2B p.Arg1074Cys Uncertain significance ★★ ⚠ same type
- TOP2B p.Arg1171Gln Uncertain significance ★★ ⚠ same type
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/top2b-p-ala490 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown