TBCK

Chr 4AR

TBC1 domain containing kinase

Also known as: FERRY1, Fy-1, HSPC302, IHPRF3, TBCKL

NCBI Gene: 93627ENSG00000145348UniProt: Q8TEA7

This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Primary Disease Associations & Inheritance

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3MIM #616900
AR
678
ClinVar variants
69
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— TBCK
🧬
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.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 237 VUS of 678 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.87LOEUF
pLI 0.000
Z-score 2.28
OE 0.65 (0.48–0.87)
Tolerant

Typical tolerance to LoF variation

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.
0.50Z-score
OE missense 0.93 (0.86–1.01)
418 obs / 448.0 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.0.65 (0.48–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.86–1.01)
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.0.99
0≤1.21.6
LoF obs/exp: 31 / 48.0Missense obs/exp: 418 / 448.0Syn Z: 0.07

ClinVar Variant Classifications

678 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic38
VUS237
Likely Benign299
Benign63
Conflicting10
31
Pathogenic
38
Likely Pathogenic
237
VUS
299
Likely Benign
63
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
0
16
0
31
Likely Pathogenic
26
0
12
0
38
VUS
2
200
33
2
237
Likely Benign
0
4
157
138
299
Benign
0
4
57
2
63
Conflicting
—10
Total43208275142678

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

View in ClinVar →

Protein Context — Lollipop Plot

TBCK · protein map & ClinVar variants

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

Gene2Phenotype Curations

TBCK-related severe infantile syndromic encephalopathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3

MIM #616900

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TBCK
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing.
Murdock DR et al.·J Clin Invest
2021Clinical trial
Expanding the genotypes and phenotypes for 19 rare diseases by exome sequencing performed in pediatric intensive care unit.
Liu J et al.·Hum Mutat
2021
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
Alazami AM et al.·Cell Rep
2015
Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review.
Sabanathan S et al.·Neuromuscul Disord
2023Review
Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice.
Nair D et al.·Am J Med Genet A
2023
Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3.
Zapata-Aldana E et al.·Eur J Med Genet
2019Review
Neurogenetic disorders associated with mutations in the FERRY complex: a novel disease class?
Riffe RM et al.·Biol Open
2025Review
A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay.
Dai H et al.·Hum Mutat
2022Cohort
Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy.
Ortiz-González XR et al.·Ann Neurol
2018
TBCK syndrome: a rare multi-organ neurodegenerative disease.
Durham EL et al.·Trends Mol Med
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
LeukodystrophyWhite Matter DiseaseLeukoencephalopathies

The Myelin Disorders Biorepository Project

RECRUITING
NCT03047369Children's Hospital of PhiladelphiaStarted 2016-12-08

External Resources

Links to major genomics databases and tools