TOP3A p.Pro874=
c.2622A>G · VCV4750876
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00267%, 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 -10 | GERP -3.4 |
| Overall | ||
| CADD | 0.026 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00267%
African / African-American · 2/74,930 alleles
Filtering AF
0.00138%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00116%
Overall
0.00167%
27/1,613,858 alleles · very rare
exomes 24/1,461,682 · genomes 3/152,176 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00267% | 37,465 |
| European (non-Finnish) | 0.00203% | 49,166 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,482 |
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
- TOP3A
- Protein
- p.Pro874=
- Coding
- c.2622A>G
- MANE Select
- NM_004618
- Type
- single nucleotide variant
- Location
- chr17:18277880 (GRCh38)
- Gene constraint
- LOEUF 0.737 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 84.14 · 2 PDB
- Residue 874
- a UniProt-annotated variant site (in peob5)
Similar variants
- TOP3A c.990+1G>T Likely pathogenic ★★ same type
- TOP3A p.Arg135Ter Pathogenic/Likely pathogenic ★★ same type
- TOP3A p.Arg177Ter Pathogenic/Likely pathogenic ★★ same type
- TOP3A p.Arg338Ter Pathogenic/Likely pathogenic ★★ same type
- TOP3A p.Ala622Thr Uncertain significance ★★ ⚠ same type
- TOP3A p.Ala642Val Uncertain significance ★★ ⚠ same type
- TOP3A p.Ala941Thr Uncertain significance ★★ ⚠ same type
- TOP3A p.Arg341Lys 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/top3a-p-pro874 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown