TOP3A
Chr 17ARDNA topoisomerase III alpha
Also known as: MGRISCE2, PEOB5, TOP3, ZGRF7
The protein functions as a DNA topoisomerase that relieves supercoiling tension during DNA replication and transcription by transiently cleaving and rejoining single DNA strands, and is essential for mitochondrial DNA decatenation and segregation. Biallelic mutations cause autosomal recessive disorders including microcephaly with growth restriction and increased sister chromatid exchange, as well as progressive external ophthalmoplegia with mitochondrial DNA deletions. This gene is highly constrained against loss-of-function mutations (pLI near 1.0), indicating intolerance to protein truncation.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.
The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 10 | 0 | 2 | 0 | 12 |
Likely Pathogenic | 2 | 1 | 0 | 0 | 3 |
VUS | 2 | 89 | 1 | 0 | 92 |
Likely Benign | 0 | 2 | 21 | 38 | 61 |
Benign | 0 | 0 | 3 | 3 | 6 |
Conflicting | — | 5 | |||
| Total | 14 | 92 | 27 | 41 | 179 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TOP3A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools