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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
TBCK
TBC1 domain containing kinase
Chromosome 4 Β· 4q24
NCBI Gene: 93627Ensembl: ENSG00000145348.17HGNC: HGNC:28261UniProt: Q5HYF5
44PubMed Papers
21Diseases
0Drugs
100Pathogenic Variants
RESEARCH IMPACT
Variant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
regulation of TOR signalingcytoplasmprotein bindingmitotic spindlehypotonia, infantile, with psychomotor retardation and characteristic facies 3hypotonia, infantile, with psychomotor retardation and characteristic faciesgenetic disorderSeizure
✦AI Summary

TBCK (TBC1 domain containing kinase) is a protein kinase that plays critical roles in neuronal function through multiple cellular mechanisms. TBCK is a component of the FERRY complex, which mediates endosomal transport of specific mRNAs by directly interacting with mRNAs and RAB5A, recruiting mRNAs and ribosomes to early endosomes 1. In neurons, TBCK preferentially localizes to endolysosomal vesicles and colocalizes with mRNA in lysosomes, facilitating mRNA transport to axonal compartments 2. Loss of TBCK leads to compartment-specific mRNA trafficking defects and lysosomal axonal retrograde trafficking defects due to reduced JIP4 levels 2. TBCK also regulates mitochondrial dynamics and membrane potential, with knockdown causing mitochondrial dysfunction that can be partially rescued by mitochondrial fission inhibitors 3. Biallelic loss-of-function mutations in TBCK cause TBCK-related encephalopathy, a rare pediatric neurodegenerative disorder characterized by hypotonia, intellectual disability, epilepsy, and hypoventilation requiring respiratory support 4. Even heterozygous TBCK variants may cause mild neurologic symptoms, including peripheral neuropathy manifestations such as acquired toe and foot deformities 5. The protein's essential role in mRNA localization and mitochondrial health makes it critical for neuronal survival and function.

Sources cited
1
TBCK is component of FERRY complex mediating endosomal mRNA transport
PMID: 37267905
2
TBCK localizes to endolysosomes, affects axonal mRNA content and lysosomal trafficking
PMID: 40093117
3
TBCK regulates mitochondrial dynamics and can be rescued with fission inhibitors
PMID: 39553985
4
Biallelic TBCK mutations cause encephalopathy with hypotonia and respiratory issues
PMID: 36522252
5
Heterozygous TBCK variants cause mild neurologic symptoms including peripheral neuropathy
PMID: 37353954
Disease Associationsβ“˜21
hypotonia, infantile, with psychomotor retardation and characteristic facies 3Open Targets
0.76Strong
hypotonia, infantile, with psychomotor retardation and characteristic faciesOpen Targets
0.55Moderate
genetic disorderOpen Targets
0.50Moderate
SeizureOpen Targets
0.43Moderate
Abnormality of the nervous systemOpen Targets
0.43Moderate
Global developmental delayOpen Targets
0.41Moderate
syndromic complex neurodevelopmental disorderOpen Targets
0.37Weak
Intellectual disabilityOpen Targets
0.34Weak
Neurodevelopmental disorderOpen Targets
0.34Weak
intestinal impactionOpen Targets
0.29Weak
HypotoniaOpen Targets
0.26Weak
atrial heart septal defectOpen Targets
0.26Weak
Complete right bundle branch blockOpen Targets
0.26Weak
Cannabis useOpen Targets
0.25Weak
polyarteritis nodosaOpen Targets
0.24Weak
asthmaOpen Targets
0.20Weak
androgenetic alopeciaOpen Targets
0.11Weak
hyperpituitarismOpen Targets
0.06Suggestive
alopeciaOpen Targets
0.05Suggestive
Left bundle branch blockOpen Targets
0.05Suggestive
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3UniProt
Pathogenic Variants100
NM_001163435.3(TBCK):c.376C>T (p.Arg126Ter)Pathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided|Inborn genetic diseases|Syndromic Infantile Encephalopathy
β˜…β˜…β˜†β˜†2026β†’ Residue 126
NM_001163435.3(TBCK):c.2252del (p.Pro751fs)Pathogenic
not provided|TBCK-related disorder|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2026β†’ Residue 751
NM_001163435.3(TBCK):c.803_806del (p.Met268fs)Pathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 1
β˜…β˜…β˜†β˜†2026β†’ Residue 268
NM_001163435.3(TBCK):c.247C>T (p.Arg83Ter)Pathogenic
Abnormality of the nervous system|not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 83
NM_001163435.3(TBCK):c.196C>T (p.Arg66Ter)Pathogenic
not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 66
NM_001163435.3(TBCK):c.456-1G>APathogenic
not provided
β˜…β˜…β˜†β˜†2025
NM_001163435.3(TBCK):c.1370dup (p.Asn457fs)Pathogenic
not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 457
NM_001163435.3(TBCK):c.1351-1G>ALikely pathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided
β˜…β˜…β˜†β˜†2025
NM_001163435.3(TBCK):c.2091dup (p.Ile698fs)Pathogenic
Inborn genetic diseases|not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 698
NM_001163435.3(TBCK):c.2060-2A>GPathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided|Ovarian serous cystadenocarcinoma
β˜…β˜…β˜†β˜†2025
NM_001163435.3(TBCK):c.382-2A>GPathogenic
not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025
NM_001163435.3(TBCK):c.1370del (p.Asn457fs)Pathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 457
NM_001163435.3(TBCK):c.1039C>T (p.Arg347Ter)Pathogenic
not provided|Global developmental delay|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 347
NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter)Pathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided|Syndromic Infantile Encephalopathy|TBCK-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 455
NM_001163435.3(TBCK):c.186_189dup (p.His64fs)Pathogenic
not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 64
NM_001163435.3(TBCK):c.1290del (p.Arg431fs)Pathogenic
not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 431
NM_001163435.3(TBCK):c.304C>T (p.Gln102Ter)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 102
NM_001163435.3(TBCK):c.1771C>T (p.Gln591Ter)Pathogenic
not provided|Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025β†’ Residue 591
NM_001163435.3(TBCK):c.531dup (p.Pro178fs)Pathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 178
NM_001163435.3(TBCK):c.456-2A>GPathogenic
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
β˜…β˜…β˜†β˜†2025
View on ClinVar β†—
Related Genes
CDC42BPGShared pathway33%TESK2Shared pathway29%CRYZL1Shared pathway25%CDC42BPAShared pathway25%NUAK2Shared pathway22%LIMK2Shared pathway22%
Tissue Expression6 tissues
Ovary
100%
Liver
56%
Heart
49%
Bone Marrow
49%
Lung
46%
Brain
44%
Gene Interaction Network
Click a node to explore
TBCKCDC42BPGTESK2CRYZL1CDC42BPANUAK2LIMK2
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q5HYF5
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
1.06LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.84 [0.66–1.06]
RankingsWhere TBCK stands among ~20K protein-coding genes
  • #9,662of 20,598
    Most Researched44
  • #779of 5,498
    Most Pathogenic Variants100 Β· top quartile
  • #10,693of 17,882
    Most Constrained (LOEUF)1.06
Genes detectedTBCK
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing.
PMID: 33001864
J Clin Invest Β· 2021
1.00
2
Expanding the genotypes and phenotypes for 19 rare diseases by exome sequencing performed in pediatric intensive care unit.
PMID: 34298581
Hum Mutat Β· 2021
0.90
3
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
PMID: 25558065
Cell Rep Β· 2015
0.80
4
A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.
PMID: 39553985
bioRxiv Β· 2024
0.70
5
TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons.
PMID: 40093117
bioRxiv Β· 2025
0.60