TOP3A

Chr 17AR

DNA topoisomerase III alpha

Also known as: MGRISCE2, PEOB5, TOP3, ZGRF7

NCBI Gene: 7156ENSG00000177302UniProt: Q13472

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

Primary Disease Associations & Inheritance

Microcephaly, growth restriction, and increased sister chromatid exchange 2MIM #618097
AR
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5MIM #618098
AR
579
ClinVar variants
116
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TOP3A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
116 Pathogenic / Likely Pathogenic· 213 VUS of 579 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.68LOEUF
pLI 0.000
Z-score 3.42
OE 0.49 (0.36–0.68)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.31Z-score
OE missense 0.85 (0.79–0.91)
493 obs / 582.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.49 (0.36–0.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.79–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 26 / 52.8Missense obs/exp: 493 / 582.0Syn Z: -1.08

ClinVar Variant Classifications

579 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic101
Likely Pathogenic15
VUS213
Likely Benign211
Benign25
Conflicting14
101
Pathogenic
15
Likely Pathogenic
213
VUS
211
Likely Benign
25
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
2
85
0
101
Likely Pathogenic
10
1
4
0
15
VUS
4
194
15
0
213
Likely Benign
0
6
75
130
211
Benign
0
5
13
7
25
Conflicting
—14
Total28208192137579

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.

Gene2Phenotype Curations

TOP3A-related Bloom syndrome like disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Microcephaly, growth restriction, and increased sister chromatid exchange 2

MIM #618097

Molecular basis of disorder known

Autosomal recessive

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

MIM #618098

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TOP3A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
Erdinc D et al.·EMBO Mol Med
2023
BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.
Tsukada K et al.·Mol Cell
2024Functional
TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT.
de Nonneville A et al.·EMBO Mol Med
2022
Functional analysis of pathological mutations in DNA topoisomerase 3A.
Wang Y et al.·Cell Rep
2025Functional
Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study.
Broberg K et al.·BMC Cancer
2009
Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder.
Jiang W et al.·Biochim Biophys Acta Mol Basis Dis
2021Case report
Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications.
Toh M et al.·Oncologist
2021Review
Chronic progressive external ophthalmoplegia plus syndrome due to homozygous missense variant in TOP3A gene.
Llauradó A et al.·Clin Genet
2023
Cardiac transplant outcomes in a pediatric patient with novel homozygous variants in TOP3Α causing mitochondrial dysfunction.
Ganesh J et al.·Mol Genet Metab
2025Case report
Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA.
Nicholls TJ et al.·Mol Cell
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools