TBCD

Chr 17AR

tubulin folding cofactor D

Also known as: PEBAT, SSD-1, tfcD

NCBI Gene: 6904 ENSG00000141556 UniProt: Q9BTW9 OMIM: 604649

Cofactor D functions as a tubulin-folding protein required for beta-tubulin assembly and microtubule dynamics, and is essential for mitotic spindle assembly and neuron morphogenesis. Biallelic mutations cause autosomal recessive progressive encephalopathy with early onset, brain atrophy, and thin corpus callosum. This gene is highly constrained against loss-of-function variants (LOEUF 0.493), indicating that heterozygous loss alone is likely detrimental.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosumMIM #617193

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome · AR · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

LOF

Mechanism· G2P

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GeneReview available — TBCD

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.82Z-score

OE missense 0.81 (0.75–0.86)

573 obs / 709.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.26–0.49)

0≤0.351.4

Missense OE?0.81 (0.75–0.86)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 26 / 73.1Missense obs/exp: 573 / 709.8Syn Z: -0.18

Background carrier burden — how many people carry a rare variant somewhere in TBCD?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 24

1,758 rare PASS variants

Rare truncating (LoF)

1 in 160

283 rare PASS variants

Rare synonymous (reference)

1 in 35

818 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBCD. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

Exome coverage (gnomAD): 32 of 39 coding exons well covered in gnomAD exomes; exons 1, 3, 8, 11, 20 and 2 more marginal. Genomes: all 39.? see exons ↓