TARDBP

Chr 1

TAR DNA binding protein

Also known as: ALS10, TDP-43

NCBI Gene: 23435 ENSG00000120948 UniProt: Q13148

The protein encoded by TARDBP is a transcriptional repressor that binds to chromosomally integrated TAR DNA to repress HIV-1 transcription and regulates alternative splicing of the CFTR gene. Mutations cause amyotrophic lateral sclerosis 10 with or without frontotemporal dementia and frontotemporal lobar degeneration through an autosomal dominant inheritance pattern. The pathogenic mechanism involves loss of function, as evidenced by the high constraint metrics indicating intolerance to loss-of-function variants.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.28

Clinical Summary— TARDBP

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis type 10 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 192 VUS of 387 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TARDBP

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.28LOEUF

pLI 0.985

Z-score 3.62

OE 0.06 (0.02–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.71Z-score

OE missense 0.32 (0.26–0.39)

74 obs / 233.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.28)

0≤0.351.4

Missense OE?0.32 (0.26–0.39)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 17.2Missense obs/exp: 74 / 233.5Syn Z: -0.75

This gene — mechanism propensity

0.4587th %ile

GOF

0.3689th %ile

LOF

0.75top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.28

GOF1 literature citation · 96% of P/LP are missense

Literature Evidence

GOFThese results suggest a toxic gain of function or dominant negative effect of mutant TDP-43.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 18309045 ↗

ClinVar Variant Classifications

387 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic17

VUS192

Likely Benign108

Benign27

Conflicting16

Pathogenic

Likely Pathogenic

192

VUS

108

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	9	0	0	9
Likely Pathogenic	1	16	0	0	17
VUS	7	131	51	3	192
Likely Benign	0	7	38	63	108
Benign	0	1	23	3	27
Conflicting	—				16
Total	8	164	112	69	369

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap TARDBP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →