TOP2B p.Pro1499=
c.4497G>A · rs557860223 · VCV1532955
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0352%, amr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>A here scores Δ0.51 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.8 | GERP -3.5 |
| Overall | ||
| CADD | 13.57 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0352%
Admixed American · 21/59,650 alleles
Filtering AF
0.0243%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0208%
Overall
0.0119%
192/1,612,158 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0352% | 2,840 |
| African / African-American | 0.0347% | 2,880 |
| Remaining individualsnot grpmax-eligible | 0.0128% | 7,799 |
| European (non-Finnish) | 0.0113% | 8,865 |
| East Asian | 0.00446% | 22,427 |
| Finnishnot grpmax-eligible | 0.00313% | 31,974 |
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.Pro1499=
- Coding
- c.4497G>A
- MANE Select
- NM_001330700
- dbSNP
- rs557860223
- Type
- single nucleotide variant
- Location
- chr3:25601218 (GRCh38)
- Gene constraint
- LOEUF 0.328 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 74.09 · 21 PDB
- Residue 1499
- the 'disordered' region
Similar variants
- TOP2B p.Pro1499Arg Uncertain significance ★ ⚠ 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-pro1499 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown