TDP2

protein-coding

tyrosyl-DNA phosphodiesterase 2

Gene summary

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]

Previous symbols:

TTRAP

MANE transcript

NM_016614.3

Inheritance

ClinVar variants

P:13U:63B:23

Top phenotype

Spinocerebellar ataxia, autosomal recessive 23

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr6:24,649,979-24,666,930

External References & Databases

Ensembl (ENSG00000111802)

Transcript & Mutation Effects

hg38 • Region Span ~17.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia, autosomal recessive 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014846

Submitter: ClinGen

*TDP2* was first reported in relation to autosomal recessive spinocerebellar ataxia 23 (MONDO:0014846) in 2014 (Gómez-Herreros *et al.*, PMID:24658003) in which siblings presented with progressive ataxia, seizures refractory to antiepileptic drugs, and intellectual disability were found to have null biallelic variants in the *TDP2* gene. Subsequent reports of individuals with pathogenic biallelic *TDP2* variants noted cerebellar ataxia, drug-resistant epilepsy, and moderate to severe intellectual disability as core clinical features with majority of the patients also presenting with craniofacial dysmorphism (PMID: 41457191). Ten variants (one missense, five nonsense, one frameshift, two splice site variants) that have been reported in eight probands in eight publications (PMIDs: 24658003, 30109272, 31410782, 32651480, 34606976, 37558815, 38433132, 41457191) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression studies and in vitro functional assays (PMID: 24658003). mRNA analyses of fetal and adult human tissue samples by Gómez-Herreros *et al.*, demonstrated that *TDP2* is highly expressed in various regions of the brain (PMID: 24658003). Moreover, neural tissue and cells of Tdp2 conditional knockout mice showed absence of 5’-TDP activity and reduced capacity for the repair of TOP2-induced double strand breaks after treatment with etoposide (PMID: 24658003). In summary, there is definitive evidence supporting the relationship between *TDP2* and autosomal recessive spinocerebellar ataxia 23. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Ataxia GCEP on the meeting date January 14th, 2026 (SOP Version 11).

spinocerebellar ataxia, autosomal recessive 23SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014846

Submitter: Orphanet

spinocerebellar ataxia, autosomal recessive 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014846

Submitter: PanelApp Australia

spinocerebellar ataxia, autosomal recessive 23MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014846

Submitter: G2P

spinocerebellar ataxia, autosomal recessive 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014846

Submitter: Ambry Genetics

spinocerebellar ataxia, autosomal recessive 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014846

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 23AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24658003

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TDP2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 52

not providedTotal: 30

not specifiedTotal: 11

Spinocerebellar ataxia, autosomal recessive 23Total: 8

TDP2-related disorderTotal: 6

Cerebellar ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016614.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	12 clinvar	1 clinvar	14
missense			57 clinvar	8 clinvar	2 clinvar	67
nonsense	5 clinvar	1 clinvar	1 clinvar			7
start loss						0
frameshift	5 clinvar					5
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	4 clinvar			6
Total	11	2	63	20	3	99

Highest pathogenic variant AF is 0.0000841284

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016614.3	RefSeq	NP_057698.2	7	MANE Select
ENST00000378198.9	Ensembl	ENSP00000367440.4	7	MANE Select
ENST00000341060.3	Ensembl	ENSP00000345345.3	6	Standard
ENST00000341060.4	Ensembl	ENSP00000345345.3	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tdp2b	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

tdp2b

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxidative Damage
DNA Repair
Nonhomologous End-Joining (NHEJ)
DNA Double-Strand Break Repair
CD40/CD40L signaling

Biological Process

double-strand break repair
cell surface receptor signaling pathway
neuron development
nucleic acid phosphodiester bond hydrolysis
negative regulation of nucleic acid-templated transcription

Molecular Function

magnesium ion binding
single-stranded DNA binding
transcription corepressor activity
nuclease activity
protein binding

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
aggresome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378198
Coding exons: 7
Length: 17057
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.115	183	187	0.976	0.00000886	2365
Missense (PolyPhen)		33	47.53	0.6943		598
Synonymous	-2.37	89	64.7	1.37	0.00000306	669
Loss of Function	1.10	15	20.4	0.737	0.00000125	229

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000090	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DNA double-strand breaks/DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Thereby, protects the transcription of many genes involved in neurological development and maintenance from the abortive activity of TOP2. Hydrolyzes 5'- phosphoglycolates on protruding 5' ends on DSBs due to DNA damage by radiation and free radicals. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Acts as a regulator of ribosome biogenesis following stress. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'- tyrosyl-DNA phosphodiesterase in cells. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non- canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:21030584, ECO:0000269|PubMed:21921940, ECO:0000269|PubMed:21980489, ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:24658003}.;
Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23) [MIM:616949]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR23 patients manifest epilepsy, intellectual disability, and gait ataxia. {ECO:0000269|PubMed:24658003}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

RVIS EVS: 1.04
RVIS percentile EVS: 91.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.824

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium