TDP1

Chr 14AR

tyrosyl-DNA phosphodiesterase 1

NCBI Gene: 55775ENSG00000042088UniProt: Q9NUW8

The protein encoded by this gene is involved in repairing stalled topoisomerase I-DNA complexes by catalyzing the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3-prime phosphate of DNA. This protein may also remove glycolate from single-stranded DNA containing 3-prime phosphoglycolate, suggesting a role in repair of free-radical mediated DNA double-strand breaks. This gene is a member of the phospholipase D family and contains two PLD phosphodiesterase domains. Mutations in this gene are associated with the disease spinocerebellar ataxia with axonal neuropathy (SCAN1). [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1MIM #607250
AR
293
ClinVar variants
24
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TDP1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 174 VUS of 293 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.
1.11LOEUF
pLI 0.000
Z-score 1.03
OE 0.82 (0.61–1.11)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.60Z-score
OE missense 0.91 (0.83–1.00)
303 obs / 333.8 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.0.82 (0.61–1.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–1.00)
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.0.95
0≤1.21.6
LoF obs/exp: 30 / 36.8Missense obs/exp: 303 / 333.8Syn Z: 0.48

ClinVar Variant Classifications

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic5
VUS174
Likely Benign34
Benign57
Conflicting4
19
Pathogenic
5
Likely Pathogenic
174
VUS
34
Likely Benign
57
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
18
0
19
Likely Pathogenic
2
1
2
0
5
VUS
3
121
46
4
174
Likely Benign
0
5
19
10
34
Benign
0
2
48
7
57
Conflicting
—4
Total513013321293

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TDP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

MIM #607250

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TDP1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks.
Geraud M et al.·Cell Rep
2024
TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes.
Paul Chowdhuri S et al.·EMBO J
2024
Genetic Homogeneity of a TDP1 Variant, c.1478A>G, as the Main Disease-Causing Variant of Spinocerebellar Ataxia With Axonal Neuropathy 1 (SCAN1) in the Middle East: A Systematic Review.
Mohammadi M et al.·Pediatr Neurol
2025Case report
Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan.
Meisenberg C et al.·Mol Cancer Ther
2015
TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.
Pir GJ et al.·FEBS J
2026Review
TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data.
Jakobsen AK et al.·Lung Cancer
2022Cohort
UCHL3 Regulates Topoisomerase-Induced Chromosomal Break Repair by Controlling TDP1 Proteostasis.
Liao C et al.·Cell Rep
2018
Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors.
Zakharova O et al.·Bioorg Med Chem
2018
[Update on hereditary neuropathy].
Nakagawa M et al.·Rinsho Shinkeigaku
2004Review
[Molecular genetics of inherited neuropathies].
Takashima H·Rinsho Shinkeigaku
2006Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
IUPAC-induced computational approaches for identifying boosters of small biomolecule functionality: A case study of human tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors.
Ivanova ML et al.·Comput Biol Med
2026Functional
Synthesis and biological evaluation of phenanthridine derivatives as dual-target inhibitors of DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), and potential antitumor agents.
Gao JM et al.·Eur J Med Chem
2026
Targeting TDP1 phosphorylation by the natural product imperatorin promotes DNA repair and cardiac regeneration.
Fu W et al.·Commun Biol
2025🔓 Open Access
Indole diketopiperazine-based hybrids with dual TDP1 and TDP2 inhibitory activities from marine fungus aspergillus sp. EGF 15-0-3.
Wei X et al.·Fitoterapia
2026
The effect of dimeric bisbenzimidazoles on the activity of DNA repair enzymes TDP1, TDP2, PARP1 and PARP2.
Dyrkheeva NS et al.·Vavilovskii Zhurnal Genet Selektsii
2025🔓 Open Access
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