TDP2

Chr 6AR

tyrosyl-DNA phosphodiesterase 2

Also known as: AD022, EAP2, EAPII, TTRAP, dJ30M3.3, hTDP2

NCBI Gene: 51567ENSG00000111802UniProt: O95551

This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Spinocerebellar ataxia, autosomal recessive 23MIM #616949
AR
105
ClinVar variants
19
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TDP2
🧬
Gene-Disease Validity (ClinGen)
spinocerebellar ataxia, autosomal recessive 23 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 59 VUS of 105 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.
1.13LOEUF
pLI 0.000
Z-score 1.10
OE 0.74 (0.49–1.13)
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.
0.11Z-score
OE missense 0.98 (0.86–1.10)
183 obs / 187.4 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.0.74 (0.49–1.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.86–1.10)
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.1.37
0≤1.21.6
LoF obs/exp: 15 / 20.4Missense obs/exp: 183 / 187.4Syn Z: -2.37

ClinVar Variant Classifications

105 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic2
VUS59
Likely Benign21
Benign6
17
Pathogenic
2
Likely Pathogenic
59
VUS
21
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
10
0
17
Likely Pathogenic
1
0
1
0
2
VUS
0
55
3
1
59
Likely Benign
0
7
2
12
21
Benign
0
3
0
3
6
Total8651616105

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

View in ClinVar →

Protein Context — Lollipop Plot

TDP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TDP2-related spinocerebellar ataxia with seizures and developmental delay

moderate
ARLoss Of FunctionAbsent Gene Product, Decreased Gene Product Level
Dev. Disorders
G2P ↗
splice region variantstop gained

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spinocerebellar ataxia, autosomal recessive 23

MIM #616949

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia.
Zagnoli-Vieira G et al.·Hum Genet
2023
TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks.
Geraud M et al.·Cell Rep
2024
Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.
Kiselev E et al.·DNA Repair (Amst)
2020
Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.
Marchand C et al.·ACS Chem Biol
2016
A novel non-sense mutation in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by bilateral upward gaze; report of a case and review of the literature.
Zoghi S et al.·Eur J Med Genet
2021Review
Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation.
Holmes AC et al.·Viruses
2020
A novel pathogenic variant in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by pituitary tumor and hyperhidrosis: a case report.
Zheng Y et al.·Neurol Sci
2024Case report
TDP2 drives immune evasion and metastatic progression in prostate cancer.
Cao H et al.·PLoS One
2026
TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1.
Zeng Z et al.·Nucleic Acids Res
2012
Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing.
Kont YS et al.·DNA Repair (Amst)
2016
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