TDP2

Chr 6AR

tyrosyl-DNA phosphodiesterase 2

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

NCBI Gene: 51567 ENSG00000111802 UniProt: O95551 OMIM: 605764

This protein is a DNA repair enzyme that removes covalent adducts from DNA by hydrolyzing 5'-phosphodiester bonds, particularly repairing topoisomerase 2-induced DNA breaks and protecting genes involved in neurological development. Mutations cause spinocerebellar ataxia with axonal neuropathy-2 (SCAN2), an autosomal recessive disorder characterized by progressive ataxia, peripheral neuropathy, and intellectual disability with childhood to adolescent onset. The gene is highly constrained against loss-of-function mutations (LOEUF 1.13), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.131 OMIM phenotype

Clinical Summary— TDP2

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Gene-Disease Validity (ClinGen)

spinocerebellar ataxia, autosomal recessive 23 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 58 VUS of 112 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.11Z-score

OE missense 0.98 (0.86–1.10)

183 obs / 187.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.49–1.13)

0≤0.351.4

Missense OE?0.98 (0.86–1.10)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 15 / 20.4Missense obs/exp: 183 / 187.4Syn Z: -2.37

ClinVar Variant Classifications

112 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic2

VUS58

Likely Benign21

Benign6

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	0	0	0	12
Likely Pathogenic	2	0	0	0	2
VUS	0	56	1	1	58
Likely Benign	0	7	2	12	21
Benign	0	3	0	3	6
Total	14	66	3	16	99

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 8) ClinVar copy-number / structural variants overlap TDP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →