TDP1

Chr 14AR

tyrosyl-DNA phosphodiesterase 1

NCBI Gene: 55775 ENSG00000042088 UniProt: Q9NUW8 OMIM: 607198

TDP1 encodes a DNA repair enzyme that removes covalent adducts from DNA by hydrolyzing 3'-phosphodiester bonds, including repair of stalled topoisomerase I-DNA complexes and radiation-induced DNA breaks. Biallelic mutations cause spinocerebellar ataxia with axonal neuropathy 1 (SCAN1), an autosomal recessive disorder affecting both the cerebellum and peripheral nerves. The gene is not highly constrained against loss-of-function variants (LOEUF 1.107), consistent with its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 1.111 OMIM phenotype

Clinical Summary— TDP1

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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

7 unique Pathogenic / Likely Pathogenic· 172 VUS of 292 total submissions

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GeneReview available — TDP1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.11LOEUF

pLI 0.000

Z-score 1.03

OE 0.82 (0.61–1.11)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.60Z-score

OE missense 0.91 (0.83–1.00)

303 obs / 333.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.61–1.11)

0≤0.351.4

Missense OE?0.91 (0.83–1.00)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 30 / 36.8Missense obs/exp: 303 / 333.8Syn Z: 0.48

ClinVar Variant Classifications

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic6

VUS172

Likely Benign33

Benign57

Conflicting4

Pathogenic

Likely Pathogenic

172

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	5	1	0	0	6
VUS	5	122	40	5	172
Likely Benign	0	5	18	10	33
Benign	0	2	48	7	57
Conflicting	—				4
Total	10	131	106	22	273

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap TDP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →