TARDBP
Chr 1ADTAR DNA binding protein
Also known as: ALS10, TDP-43
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.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
440 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 9 | 30 | 0 | 39 |
Likely Pathogenic | 1 | 15 | 8 | 0 | 24 |
VUS | 8 | 131 | 67 | 3 | 209 |
Likely Benign | 0 | 7 | 38 | 63 | 108 |
Benign | 0 | 1 | 23 | 3 | 27 |
Conflicting | — | 15 | |||
| Total | 9 | 163 | 166 | 69 | 422 |
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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Amyotrophic Lateral Sclerosis (ALS) Families Project
RECRUITINGAn Innovative Method in SAliva Samples for the Early Differential Diagnosis of High-impact NeuroDegenerative Diseases Through Raman Spectroscopy
ENROLLING BY INVITATIONLongitudinal Assessment of Autonomic and Sensory Nervous System in ALS
RECRUITINGTracking and Predicting How Brain Damage Spreads in Neurodegenerative Diseases
ENROLLING BY INVITATIONExternal Resources
Links to major genomics databases and tools