TBCD

Chr 17AR

tubulin folding cofactor D

Also known as: PEBAT, SSD-1, tfcD

NCBI Gene: 6904ENSG00000141556UniProt: Q9BTW9

Cofactor D is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosumMIM #617193
AR
1694
ClinVar variants
35
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TBCD
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
35 Pathogenic / Likely Pathogenic· 161 VUS of 1694 total submissions

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.
0.49LOEUF
pLI 0.000
Z-score 5.11
OE 0.36 (0.26–0.49)
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.
1.82Z-score
OE missense 0.81 (0.75–0.86)
573 obs / 709.8 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.0.36 (0.26–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.75–0.86)
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: 26 / 73.1Missense obs/exp: 573 / 709.8Syn Z: -0.18

ClinVar Variant Classifications

1694 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic7
VUS161
Likely Benign248
Benign8
Conflicting3
28
Pathogenic
7
Likely Pathogenic
161
VUS
248
Likely Benign
8
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
1
19
0
28
Likely Pathogenic
4
0
3
0
7
VUS
1
145
15
0
161
Likely Benign
0
13
111
124
248
Benign
0
3
3
2
8
Conflicting
—3
Total13162151126455

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

View in ClinVar →

Protein Context — Lollipop Plot

TBCD · protein map & ClinVar variants

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

Gene2Phenotype Curations

TBCD-related early-onset neurodegenerative 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

Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum

MIM #617193

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
PEBAT, an Intriguing Neurodegenerative Tubulinopathy Caused by a Novel Homozygous Variant in TBCD: A Case Series and Literature Review.
Ocampo-Chih C et al.·Pediatr Neurol
2023Review
Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.
Martínez-Rubio D et al.·Int J Mol Sci
2023
Developmental Regression and Epilepsy of Infancy with Migrating Focal Seizures Caused by TBCD Mutation: A Case Report and Review of the Literature.
Zhang Y et al.·Neuropediatrics
2020Review
CRISPR/Cas9 and piggyBac Transposon-Based Conversion of a Pathogenic Biallelic TBCD Variant in a Patient-Derived iPSC Line Allows Correction of PEBAT-Related Endophenotypes.
Muto V et al.·Int J Mol Sci
2023
Dynamically monitoring minimal residual disease using circulating tumour cells to predict the recurrence of early-stage lung adenocarcinoma.
Zhang Q et al.·J Hematol Oncol
2024
A Variant in TBCD Associated with Motoneuronopathy and Corpus Callosum Hypoplasia: A Case Report.
Caputo M et al.·Int J Mol Sci
2023Case report
A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.
Grønborg S et al.·Eur J Hum Genet
2018
Biallelic pathogenic variants in TBCD-related neurodevelopment disease with mild clinical features.
Tian D et al.·Neurol Sci
2019Case report
Genotype variability in early-onset Hereditary Spastic Paraplegia: a single-center study.
Colona VL et al.·Eur J Paediatr Neurol
2025
Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.
Stephen J et al.·BMC Med Genet
2018Case report
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools