TARDBP

Chr 1AD

TAR DNA binding protein

Also known as: ALS10, TDP-43

NCBI Gene: 23435 ENSG00000120948 UniProt: Q13148 OMIM: 605078

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 10, with or without FTDMIM #612069

Frontotemporal lobar degeneration, TARDBP-relatedMIM #612069

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · amyotrophic lateral sclerosis type 10 · AD · ClinGen 2021

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

128

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — TARDBP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in TARDBP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

292 rare PASS variants

Rare truncating (LoF)

1 in 2,900

23 rare PASS variants

Rare synonymous (reference)

1 in 140

228 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TARDBP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 200	1 in 2,900
South Asian	~43k	1 in 150	1 in 2,100
Remaining (unassigned)	~30k	1 in 190	none seen
European (Finnish)	~27k	1 in 320	none seen
Admixed American	~22k	1 in 290	≈ 1 in 18,000
African / African American	~21k	1 in 400	1 in 2,300
East Asian	~20k	1 in 220	1 in 820
Ashkenazi Jewish	~13k	≈ 1 in 4,200	none seen
Middle Eastern	~2,884	1 in 220	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓