TBCK

Chr 4AR

TBC1 domain containing kinase

Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary) (PubMed:37267905). The FERRY complex directly interacts with mRNAs and RAB5A, and functions as a RAB5A effector involved in the localization and the distribution of specific mRNAs most likely by mediating their endosomal transport. The complex recruits mRNAs and ribosomes to early endosomes through direct mRNA-interaction (PubMed:37267905). Also involved in the modulation of mTOR signaling and expression of mTOR complex components (PubMed:23977024, PubMed:27040691). Involved in the control of actin-cytoskeleton organization (PubMed:23977024)

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismARLOEUF 0.871 OMIM phenotype
Clinical SummaryTBCK
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Gene-Disease Validity (ClinGen)
syndromic complex neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
112 unique Pathogenic / Likely Pathogenic· 275 VUS of 855 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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GeneReview available — TBCK
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?
0.87LOEUF
pLI 0.000
Z-score 2.28
OE 0.65 (0.480.87)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
0.50Z-score
OE missense 0.93 (0.861.01)
418 obs / 448.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.65 (0.480.87)
00.351.4
Missense OE?0.93 (0.861.01)
00.61.4
Synonymous OE?0.99
01.21.6
LoF obs/exp: 31 / 48.0Missense obs/exp: 418 / 448.0Syn Z: 0.07
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTBCK-related severe infantile syndromic encephalopathyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6936th %ile
GOF
0.6540th %ile
LOF
0.2872th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

855 submitted variants in ClinVar

Classification Summary

Pathogenic54
Likely Pathogenic58
VUS275
Likely Benign358
Benign72
Conflicting16
54
Pathogenic
58
Likely Pathogenic
275
VUS
358
Likely Benign
72
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
43
0
11
0
54
Likely Pathogenic
50
1
7
0
58
VUS
2
243
28
2
275
Likely Benign
0
8
186
164
358
Benign
0
5
60
7
72
Conflicting
16
Total95257292173833

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap TBCK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TBCK · protein map & ClinVar variants

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