TBK1

Chr 12ADAR

TANK binding kinase 1

Also known as: AIARV, FTDALS4, IIAE8, NAK, T2K

NCBI Gene: 29110 ENSG00000183735 UniProt: Q9UHD2

The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response. [provided by RefSeq, Sep 2021]

Primary Disease Associations & Inheritance

{Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}MIM #617900

Autoinflammation with arthritis and vasculitisMIM #620880

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4MIM #616439

UniProtGlaucoma 1, open angle, P

582

ClinVar variants

Pathogenic / LP

0.08

pLI score

Active trials

Clinical Summary— TBK1

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Gene-Disease Validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

84 Pathogenic / Likely Pathogenic· 271 VUS of 582 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.42LOEUF

pLI 0.075

Z-score 4.55

OE 0.25 (0.16–0.42)

Moderately constrained

More LoF-intolerant than ~75% 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.

1.93Z-score

OE missense 0.72 (0.65–0.79)

267 obs / 372.0 exp

Tolerant

Mild missense constraint

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.0.25 (0.16–0.42)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.65–0.79)

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.1.01

0≤1.21.6

LoF obs/exp: 11 / 43.3Missense obs/exp: 267 / 372.0Syn Z: -0.06