TOP2A p.Lys976=
c.2928A>G · rs34273139 · VCV768880
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
low-frequency (popmax 3.39%, afr)
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 -0.57, phastCons 0.001 |
| Overall | ||
| CADD | 4.174 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
3.39%
African / African-American · 2,546/75,016 alleles
Filtering AF
3.28%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 3.24%
Overall
0.184%
2,974/1,613,862 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 3.39% | 29 |
| Remaining individualsnot grpmax-eligible | 0.277% | 361 |
| Admixed American | 0.203% | 492 |
| Middle Eastern | 0.182% | 551 |
| European (non-Finnish) | 0.00983% | 10,171 |
| South Asian | 0.00439% | 22,769 |
| Finnishnot grpmax-eligible | 0.00312% | 32,001 |
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.Lys976=
- Coding
- c.2928A>G
- MANE Select
- NM_001067
- dbSNP
- rs34273139
- Type
- single nucleotide variant
- Location
- chr17:40400281 (GRCh38)
- Gene constraint
- LOEUF 0.422 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 75.33 · 15 PDB
- Residue 976
- the topo iia-type catalytic domain; 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.Pro643= Likely 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-lys976 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown