TARDBP

Chr 1AD

TAR DNA binding protein

Also known as: ALS10, TDP-43

NCBI Gene: 23435ENSG00000120948UniProt: Q13148

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]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 10, with or without FTDMIM #612069
AD
Frontotemporal lobar degeneration, TARDBP-relatedMIM #612069
AD
417
ClinVar variants
63
Pathogenic / LP
0.99
pLI score· haploinsufficient
3
Active trials
Clinical Summary— TARDBP
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 10 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
63 Pathogenic / Likely Pathogenic· 206 VUS of 417 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.32 (0.26–0.39)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 1 / 17.2Missense obs/exp: 74 / 233.5Syn Z: -0.75

ClinVar Variant Classifications

417 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic24
VUS206
Likely Benign107
Benign27
Conflicting14
39
Pathogenic
24
Likely Pathogenic
206
VUS
107
Likely Benign
27
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
9
30
0
39
Likely Pathogenic
1
15
8
0
24
VUS
3
126
75
2
206
Likely Benign
0
7
38
62
107
Benign
0
1
23
3
27
Conflicting
—14
Total415817467417

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

View in ClinVar →

Protein Context — Lollipop Plot

TARDBP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Amyotrophic lateral sclerosis 10, with or without FTD

MIM #612069

Molecular basis of disorder known

Autosomal dominant

Frontotemporal lobar degeneration, TARDBP-related

MIM #612069

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TARDBP
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].
Meyer T·Dtsch Med Wochenschr
2021Review
The genetics of amyotrophic lateral sclerosis.
Nijs M et al.·Curr Opin Neurol
2024Review
Amyotrophic lateral sclerosis.
Wijesekera LC et al.·Orphanet J Rare Dis
2009Review
Autophagy and ALS: mechanistic insights and therapeutic implications.
Chua JP et al.·Autophagy
2022Review
ALS Genetics: Gains, Losses, and Implications for Future Therapies.
Kim G et al.·Neuron
2020Review
Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration.
Rusmini P et al.·Autophagy
2019Functional
Evidence-based consensus guidelines for ALS genetic testing and counseling.
Roggenbuck J et al.·Ann Clin Transl Neurol
2023
Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice.
Benzow K et al.·Alzheimers Dement
2024Functional
Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.
Chen YP et al.·J Med Genet
2022Cohort
TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.
Arseni D et al.·Nature
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Neurodegenerative DisordersParkinson DiseaseAlzheimer Disease

An Innovative Method in SAliva Samples for the Early Differential Diagnosis of High-impact NeuroDegenerative Diseases Through Raman Spectroscopy

ENROLLING BY INVITATION
NCT06875739Fondazione Don Carlo Gnocchi OnlusStarted 2025-02-14
ALS

Amyotrophic Lateral Sclerosis (ALS) Families Project

RECRUITING
NCT03865420Columbia UniversityStarted 2018-09-11
Amyotrophic Lateral Sclerosis

Longitudinal Assessment of Autonomic and Sensory Nervous System in ALS

RECRUITING
NCT05747937Phase NAIstituti Clinici Scientifici Maugeri SpAStarted 2021-05-15
Skin biopsyCardiovascular Reflexes testingAdministration of clinical scales evaluating autonomic symptoms, pain small fiber neuropathy symptoms

External Resources

Links to major genomics databases and tools