TOP2A p.Pro643=
c.1929T>G · rs1598615707 · VCV726507
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.505%, nfe)
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 0.24 | GERP 1.9, phastCons 0.24 |
| Overall | ||
| CADD | 8.365 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.505%
European (non-Finnish) · 5,793/1,146,660 alleles
Filtering AF
0.494%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.49%
Overall
0.435%
6,844/1,573,794 alleles · rare
exomes 6,811/1,421,802 · genomes 33/151,992 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.505% | 198 |
| East Asian | 0.461% | 217 |
| Remaining individualsnot grpmax-eligible | 0.421% | 238 |
| Finnishnot grpmax-eligible | 0.33% | 303 |
| Ashkenazi Jewishnot grpmax-eligible | 0.314% | 319 |
| Middle Eastern | 0.235% | 425 |
| African / African-American | 0.185% | 542 |
| South Asian | 0.107% | 931 |
| Admixed American | 0.0806% | 1,240 |
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
- TOP2A
- Protein
- p.Pro643=
- Coding
- c.1929T>G
- MANE Select
- NM_001067
- dbSNP
- rs1598615707
- Type
- single nucleotide variant
- Location
- chr17:40406408 (GRCh38)
- Gene constraint
- LOEUF 0.422 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 75.33 · 15 PDB
- Residue 643
- an α-helix
Similar variants
- TOP2A p.Pro1194Arg Uncertain significance ★★ ⚠ same type
- TOP2A p.Ala243= Benign ★★ same type
- TOP2A p.Asn774Ile Likely benign ★★ same type
- TOP2A p.Glu571= Benign ★★ same type
- TOP2A p.Gly1197Ala Likely benign ★★ same type
- TOP2A p.Gly1197Glu Likely benign ★★ same type
- TOP2A p.Lys976= Benign ★★ same type
- TOP2A p.Ser390= Benign/Likely benign ★★ 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/top2a-p-pro643 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown