TBCD

Summary

TBCD (tubulin folding cofactor D, HGNC:11581) is a protein-coding gene on chromosome 17q25.3, encoding Tubulin-specific chaperone D (Q9BTW9). Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly. It is a common-essential gene (DepMap: required in 97.0% of cancer cell lines).

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.

Source: NCBI Gene 6904 — RefSeq curated summary.

At a glance

• Gene–disease (curated): early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 1,539 total — 65 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 87
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_005993

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11581
Approved symbol	TBCD
Name	tubulin folding cofactor D
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141556
Ensembl biotype	protein_coding
OMIM	604649
Entrez	6904

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 43 protein_coding, 14 retained_intron, 12 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay

ENST00000355528, ENST00000539345, ENST00000570679, ENST00000571316, ENST00000571618, ENST00000571712, ENST00000571796, ENST00000572389, ENST00000572794, ENST00000572953, ENST00000572984, ENST00000573364, ENST00000574422, ENST00000574801, ENST00000574818, ENST00000574886, ENST00000574975, ENST00000575132, ENST00000576160, ENST00000576432, ENST00000576603, ENST00000576677, ENST00000576691, ENST00000576760, ENST00000576996, ENST00000577051, ENST00000681983, ENST00000682099, ENST00000682107, ENST00000682213, ENST00000682225, ENST00000682315, ENST00000682479, ENST00000682610, ENST00000682654, ENST00000682722, ENST00000682921, ENST00000682934, ENST00000683009, ENST00000683041, ENST00000683184, ENST00000683282, ENST00000683444, ENST00000683584, ENST00000683821, ENST00000683839, ENST00000683883, ENST00000684000, ENST00000684188, ENST00000684349, ENST00000684361, ENST00000684408, ENST00000684429, ENST00000684464, ENST00000684544, ENST00000684559, ENST00000684760, ENST00000684776, ENST00000857308, ENST00000857309, ENST00000857310, ENST00000857311, ENST00000857312, ENST00000857313, ENST00000857314, ENST00000857315, ENST00000857316, ENST00000915788, ENST00000915789, ENST00000915790, ENST00000915791, ENST00000959286, ENST00000959287, ENST00000959288, ENST00000959289, ENST00000959290

RefSeq mRNA: 3 — MANE Select: NM_005993 NM_001411101, NM_001411102, NM_005993

CCDS: CCDS45818, CCDS92421, CCDS92423

Canonical transcript exons

ENST00000355528 — 39 exons

Exon	Start	End
ENSE00001312642	82752065	82752377
ENSE00001463825	82942449	82945914
ENSE00002444029	82929362	82929500
ENSE00002461837	82930522	82930643
ENSE00002725063	82814840	82814934
ENSE00003467950	82870224	82870380
ENSE00003473529	82905936	82906053
ENSE00003474227	82924939	82925057
ENSE00003481065	82893547	82893632
ENSE00003484080	82939367	82939476
ENSE00003490590	82763965	82764062
ENSE00003491515	82797757	82797802
ENSE00003508320	82929113	82929271
ENSE00003521041	82927186	82927323
ENSE00003523906	82923652	82923733
ENSE00003525355	82921501	82921577
ENSE00003526131	82809708	82809782
ENSE00003534217	82909285	82909307
ENSE00003544622	82927905	82927988
ENSE00003548239	82805875	82806011
ENSE00003551641	82807608	82807668
ENSE00003556099	82932658	82932735
ENSE00003560643	82903405	82903478
ENSE00003560942	82772452	82772507
ENSE00003569900	82781589	82781721
ENSE00003574335	82756165	82756215
ENSE00003577294	82938049	82938136
ENSE00003580913	82937271	82937360
ENSE00003581612	82907761	82907821
ENSE00003589111	82884145	82884202
ENSE00003616641	82911758	82911789
ENSE00003618552	82768420	82768566
ENSE00003622351	82920556	82920618
ENSE00003625346	82766267	82766368
ENSE00003629520	82900651	82900731
ENSE00003648843	82926400	82926491
ENSE00003663039	82889668	82889697
ENSE00003682883	82800864	82800996
ENSE00003690374	82941399	82941483

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.6478 / max 293.6568, expressed in 1817 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163546	36.7605	1814
163545	1.6083	794
163557	0.8650	218
163564	0.5383	211
163554	0.4873	168
163556	0.1182	64
163563	0.1036	60
163567	0.0789	35
163562	0.0404	28
163568	0.0332	10

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	98.23	gold quality
apex of heart	UBERON:0002098	98.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.05	gold quality
left lobe of thyroid gland	UBERON:0001120	97.98	gold quality
endocervix	UBERON:0000458	97.89	gold quality
adenohypophysis	UBERON:0002196	97.80	gold quality
right uterine tube	UBERON:0001302	97.71	gold quality
cerebellar hemisphere	UBERON:0002245	97.66	gold quality
granulocyte	CL:0000094	97.62	gold quality
ectocervix	UBERON:0012249	97.59	gold quality
ventricular zone	UBERON:0003053	97.58	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.51	gold quality
cerebellar cortex	UBERON:0002129	97.44	gold quality
body of uterus	UBERON:0009853	97.40	gold quality
minor salivary gland	UBERON:0001830	97.31	gold quality
lower esophagus mucosa	UBERON:0035834	97.26	gold quality
tibial nerve	UBERON:0001323	97.21	gold quality
body of stomach	UBERON:0001161	97.02	gold quality
gall bladder	UBERON:0002110	96.97	gold quality
right ovary	UBERON:0002118	96.97	gold quality
right frontal lobe	UBERON:0002810	96.92	gold quality
left ovary	UBERON:0002119	96.89	gold quality
left uterine tube	UBERON:0001303	96.68	gold quality
skin of leg	UBERON:0001511	96.65	gold quality
left testis	UBERON:0004533	96.54	gold quality
mucosa of stomach	UBERON:0001199	96.53	gold quality
lower esophagus	UBERON:0013473	96.53	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.53	gold quality
ganglionic eminence	UBERON:0004023	96.51	gold quality
omental fat pad	UBERON:0010414	96.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.72
E-MTAB-6911	no	189.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting TBCD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-1251-5P	95.78	64.10	374

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 15)

• provides first evidence that beta-tubulin cofactor D plays a role in cells independent of its presumed role in folding tubulin heterodimers (PMID:17704193)
• Cofactor D functions as a centrosomal protein and is required for the recruitment of the gamma-tubulin ring complex at centrosomes and organization of the mitotic spindle (PMID:18171676)
• Data show that bovine and human TBCD have functionally identical roles in tubulin heterodimer assembly, and that the inability of human TBCD to disrupt microtubule integrity can be overcome by siRNA-mediated suppression of expression of Arl2. (PMID:20740604)
• genetic polymorphism is associated with bone mineral accretion in children with asthma receiving intermittent oral corticosteroids (PMID:26025128)
• Results identified ARL2 and TBCD, as important in tubulin folding and microtubule dynamics. Both ARL2 and TBCD also localize to centrosomes. [review] (PMID:27400436)
• findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain (PMID:27666370)
• Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of a neurodegenerative encephalopathy. (PMID:27666374)
• Intractable epilepsy, intellectual disability and acquired microcephaly, and cortical atrophy and thinned corpus callosum as major MRI features, caused by biallelic variants in TBCD. (PMID:27807845)
• variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. (PMID:27928163)
• Authors conclude that TBCD is a novel functional contributor to the mammalian cerebral cortex development, and that the pathological mechanism resulting from the mutations we describe is likely to involve compromised interactions with one or more TBCD-interacting effectors that influence the dynamics and behaviour of the neuronal cytoskeleton. (PMID:28158450)
• TBCD protein was localized in the middle region and in the tail of the sperm while in the oocyte the localization was cytosolic. (PMID:28583220)
• conclude that the TBCD*ARL2*beta-tubulin complex represents a functional intermediate in the beta-tubulin folding pathway whose activity is regulated by the cycling of nucleotides on ARL2 (PMID:28970104)
• Study identified a homozygous novel pathogenic missense mutation (c.1423G > A;p.Ala475Thr) in TBCD gene to be associated with concurrent hypofibrinogenemia and cortical atrophy. (PMID:29769041)
• We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples. (PMID:29921875)
• [MOH SCREENING FOR TBCD IN COCHIN JEWS: COLLABORATION BETWEEN MEDICAL, RESEARCH AND COMMUNITY MEMBERS IN ACHIEVING PUBLIC HEALTH GOALS]. (PMID:37394437)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbcd	ENSDARG00000098749
mus_musculus	Tbcd	ENSMUSG00000039230
rattus_norvegicus	Tbcd	ENSRNOG00000036658
drosophila_melanogaster	Tbcd	FBGN0027509
caenorhabditis_elegans	tbcd-1	WBGENE00008887

Protein

Protein identifiers

Tubulin-specific chaperone D — Q9BTW9 (reviewed: Q9BTW9)

Alternative names: Beta-tubulin cofactor D, SSD-1, Tubulin-folding cofactor D

All UniProt accessions (31): A0A804HHW7, A0A804HI02, A0A804HI57, A0A804HIC0, A0A804HIN6, A0A804HIU1, Q9BTW9, A0A804HJ32, A0A804HJ57, A0A804HJ99, A0A804HJL5, A0A804HJU6, A0A804HJY5, A0A804HK36, A0A804HKB9, A0A804HKT8, A0A804HL21, A0A804HL62, A0A804HLF8, A0A804HLI2, I3L0V3, I3L120, I3L131, I3L143, I3L163, I3L1L0, I3L1S3, I3L3H4, I3L439, I3L4D2, J3KR97

UniProt curated annotations — full annotation on UniProt →

Function. Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly. Involved in the regulation of microtubule polymerization or depolymerization, it modulates microtubule dynamics by capturing GTP-bound beta-tubulin (TUBB). Its ability to interact with beta tubulin is regulated via its interaction with ARL2. Acts as a GTPase-activating protein (GAP) for ARL2. Induces microtubule disruption in absence of ARL2. Increases degradation of beta tubulin, when overexpressed in polarized cells. Promotes epithelial cell detachment, a process antagonized by ARL2. Induces tight adherens and tight junctions disassembly at the lateral cell membrane. Required for correct assembly and maintenance of the mitotic spindle, and proper progression of mitosis. Involved in neuron morphogenesis.

Subunit / interactions. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Interacts with PPP2CB. Part of a supercomplex made of cofactors A to E. Cofactors A and D function by capturing and stabilizing tubulin in a quasi-native conformation. Cofactor E binds to the cofactor D-tubulin complex; interaction with cofactor C then causes the release of tubulin polypeptides that are committed to the native state. Interacts with ARL2; interaction is enhanced with the GDP-bound form of ARL2. Does not interact with ARL3, ARL4A and ARL4D. Interacts with beta tubulin. Interacts with TBCE.

Subcellular location. Cell junction. Tight junction. Lateral cell membrane. Cytoplasm. Adherens junction. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum (PEBAT) [MIM:617193] An autosomal recessive disease with neurodevelopmental and neurodegenerative features. PEBAT is characterized by early-onset cortical atrophy, hypomyelination, microcephaly, thin corpus callosum, delayed psychomotor development, developmental regression, intellectual disability, seizures, optic atrophy, muscle weakness and atrophy, spastic quadriplegia, and respiratory insufficiency due to hypotonia. The disease is caused by variants affecting the gene represented in this entry.

Induction. Down-regulated by shear stress.

Similarity. Belongs to the TBCD family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9BTW9-1	1	yes
Q9BTW9-2	2
Q9BTW9-3	3
Q9BTW9-4	4
Q9BTW9-5	5

RefSeq proteins (3): NP_001398030, NP_001398031, NP_005984* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR022577	TBCD_C	Domain
IPR033162	TBCD	Family
IPR058033	ARM_TBCD_2nd	Domain

Pfam: PF12612, PF23579, PF25767

UniProt features (37 total): sequence variant 17, splice variant 9, sequence conflict 7, repeat 3, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9M1J	ELECTRON MICROSCOPY	2.14
9M1M	ELECTRON MICROSCOPY	2.21
9M1N	ELECTRON MICROSCOPY	2.24
9M1K	ELECTRON MICROSCOPY	2.45
9M1I	ELECTRON MICROSCOPY	2.48
9M1L	ELECTRON MICROSCOPY	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTW9-F1	90.45	0.77

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-389977	Post-chaperonin tubulin folding pathway
R-HSA-391251	Protein folding
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 382 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_NEUROGENESIS, MODULE_16, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_CELL_SUBSTRATE_ADHESION, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_PROTEIN_MATURATION, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_ADHERENS_JUNCTION_ASSEMBLY

GO Biological Process (10): microtubule cytoskeleton organization (GO:0000226), mitotic cell cycle (GO:0000278), protein folding (GO:0006457), tubulin complex assembly (GO:0007021), post-chaperonin tubulin folding pathway (GO:0007023), negative regulation of cell-substrate adhesion (GO:0010812), negative regulation of microtubule polymerization (GO:0031115), adherens junction assembly (GO:0034333), cell morphogenesis involved in neuron differentiation (GO:0048667), bicellular tight junction assembly (GO:0070830)

GO Molecular Function (4): GTPase activator activity (GO:0005096), beta-tubulin binding (GO:0048487), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), centrosome (GO:0005813), microtubule (GO:0005874), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), lateral plasma membrane (GO:0016328), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein folding	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoskeleton organization	1
microtubule-based process	1
cell cycle	1
mitotic nuclear division	1
cellular process	1
protein maturation	1
protein-containing complex assembly	1
tubulin complex assembly	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
negative regulation of microtubule polymerization or depolymerization	1
regulation of microtubule polymerization	1
negative regulation of protein polymerization	1
microtubule polymerization	1
negative regulation of supramolecular fiber organization	1
cell-cell junction assembly	1
adherens junction organization	1
cell morphogenesis	1
neuron differentiation	1
neuron development	1
apical junction assembly	1
tight junction assembly	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
tubulin binding	1
protein binding	1
binding	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
cell-cell junction	1
apical junction complex	1
tight junction	1
plasma membrane	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBCD	A0A2R8Y809	A0A2R8Y809	950
TBCD	TBCE	Q15813	950
TBCD	TBCEL	Q5QJ74	889
TBCD	ARL2	P36404	835
TBCD	TBCB	Q99426	776
TBCD	CPN1	P15169	764
TBCD	TBCC	Q15814	736
TBCD	SLITRK2	Q9H156	675
TBCD	NPTX1	Q15818	666
TBCD	IMMP2L	Q96T52	662
TBCD	HDC	P19113	652
TBCD	DSCAM	O60469	621
TBCD	SLITRK1	Q96PX8	619
TBCD	TUBB2A	Q13885	612
TBCD	TBCA	O75347	603

IntAct

87 interactions, top by confidence:

A	B	Type	Score
ARL2	TBCD	psi-mi:“MI:0407”(direct interaction)	0.690
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
ARL2	TUBB4A	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
TUBB2A	EML2	psi-mi:“MI:0914”(association)	0.530
TUBB2B	EML2	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
IL1R2	EXOC5	psi-mi:“MI:0914”(association)	0.530
TUBB2A	ARL2	psi-mi:“MI:0914”(association)	0.530
ACD	TBCD	psi-mi:“MI:0915”(physical association)	0.510
ARL3	TBCD	psi-mi:“MI:0407”(direct interaction)	0.440
TBCD	H4C16	psi-mi:“MI:0915”(physical association)	0.400
Tubb5		psi-mi:“MI:0915”(physical association)	0.400
Tubb4b	MGST3	psi-mi:“MI:0915”(physical association)	0.400
TERF1	TBCD	psi-mi:“MI:0915”(physical association)	0.370
TBCD	POT1	psi-mi:“MI:0915”(physical association)	0.370
POLR2I	TBCD	psi-mi:“MI:0915”(physical association)	0.370
TBCD	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
ORF4	DNM1L	psi-mi:“MI:0914”(association)	0.350
SH2D3C	TMEM14DP	psi-mi:“MI:0914”(association)	0.350
RAC1		psi-mi:“MI:0914”(association)	0.350
PRKCB	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
PA	ESYT2	psi-mi:“MI:0914”(association)	0.350
CTDP1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SMIM26	CNOT1	psi-mi:“MI:0914”(association)	0.350
CLINT1	MAP4	psi-mi:“MI:0914”(association)	0.350
MAP4	TUBA1B	psi-mi:“MI:0914”(association)	0.350
TUBB4B	TUBA1B	psi-mi:“MI:0914”(association)	0.350

BioGRID (177): TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS), ARL2 (Co-fractionation), TBCD (Co-fractionation), TPM3 (Co-fractionation), TPM4 (Co-fractionation), TBCD (Affinity Capture-MS), TBCD (Synthetic Lethality), TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS), TBCD (Affinity Capture-MS)

ESM2 similar proteins: A0A0U3BRC5, A0A2L0VXR5, A2AIL4, A7YVD7, A9UMP7, C5Y210, D3ZN43, E7FCP8, F4I1L3, K2SUY0, M2U578, O43824, O95822, Q08BC6, Q15118, Q16854, Q1LXS2, Q28205, Q2KHV5, Q2QMG2, Q330K2, Q39108, Q4KM93, Q53S58, Q5ZM96, Q6DCC6, Q6JQN1, Q7XYS8, Q8BPE4, Q8K370, Q8N159, Q8R4H7, Q8RWT8, Q8S6N5, Q920F5, Q96RQ3, Q99J39, Q99MR8, Q9BTW9, Q9CWG8

Diamond homologs: Q28205, Q5ZI87, Q8BYA0, Q8L5R3, Q9BTW9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	7	58.6×	2e-09
Transport of connexons to the plasma membrane	7	58.6×	2e-09
Gap junction trafficking and regulation	7	51.2×	4e-09
Gap junction trafficking	7	51.2×	4e-09
Post-chaperonin tubulin folding pathway	7	51.2×	4e-09
Formation of tubulin folding intermediates by CCT/TriC	7	45.5×	7e-09
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	7	43.9×	8e-09
RHO GTPases activate IQGAPs	8	42.6×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
microtubule cytoskeleton organization	9	11.4×	7e-05
mitotic cell cycle	7	9.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1539 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	65
Likely pathogenic	34
Uncertain significance	429
Likely benign	779
Benign	129

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030991	NM_005993.5(TBCD):c.1957C>T (p.Gln653Ter)	Pathogenic
1295	NM_024702.3(ZNF750):c.55_56dup (p.Gly20fs)	Pathogenic
1459481	NC_000017.10:g.(?80710070)(80724264_?)del	Pathogenic
1700434	NM_005993.5(TBCD):c.1306C>T (p.Arg436Ter)	Pathogenic
1707501	NM_005993.5(TBCD):c.1006C>T (p.Gln336Ter)	Pathogenic
1967212	NM_005993.5(TBCD):c.3461_3462del (p.Val1154fs)	Pathogenic
1975424	NM_005993.5(TBCD):c.1738C>T (p.Arg580Ter)	Pathogenic
2108292	NM_005993.5(TBCD):c.2725C>T (p.Gln909Ter)	Pathogenic
2425451	NC_000017.10:g.(?80710070)(80901020_?)del	Pathogenic
2425452	NC_000017.10:g.(?80851403)(80851528_?)del	Pathogenic
2425453	NC_000017.10:g.(?80847524)(80901020_?)del	Pathogenic
268166	NM_005993.5(TBCD):c.1564-12C>G	Pathogenic
268168	NM_005993.5(TBCD):c.2761G>A (p.Ala921Thr)	Pathogenic
268169	NM_005993.5(TBCD):c.1160T>G (p.Met387Arg)	Pathogenic
268170	NM_005993.5(TBCD):c.2280C>A (p.Tyr760Ter)	Pathogenic
268172	NM_005993.5(TBCD):c.2810C>G (p.Pro937Arg)	Pathogenic
268175	NM_005993.5(TBCD):c.1130G>A (p.Arg377Gln)	Pathogenic
2700170	NM_005993.5(TBCD):c.1681C>T (p.Gln561Ter)	Pathogenic
2710480	NM_005993.5(TBCD):c.1939_1940del (p.Leu647fs)	Pathogenic
2711799	NM_005993.5(TBCD):c.896del (p.Lys299fs)	Pathogenic
2716645	NM_005993.5(TBCD):c.16G>T (p.Glu6Ter)	Pathogenic
2719123	NM_005993.5(TBCD):c.3256C>T (p.Gln1086Ter)	Pathogenic
2739398	NM_005993.5(TBCD):c.1447dup (p.Leu483fs)	Pathogenic
2744108	NM_005993.5(TBCD):c.1543C>T (p.Gln515Ter)	Pathogenic
2750093	NM_005993.5(TBCD):c.3034dup (p.Ile1012fs)	Pathogenic
2753842	NM_005993.5(TBCD):c.29del (p.Gly10fs)	Pathogenic
2758224	NM_005993.5(TBCD):c.1527del (p.Ala510fs)	Pathogenic
2765107	NM_005993.5(TBCD):c.817+1G>A	Pathogenic
2779835	NM_005993.5(TBCD):c.2004_2005insT (p.Arg669Ter)	Pathogenic
2782388	NM_005993.5(TBCD):c.1220dup (p.Ser408fs)	Pathogenic

SpliceAI

11752 predictions. Top by Δscore:

Variant	Effect	Δscore
17:82752326:G:GT	donor_gain	1.0000
17:82756163:A:AG	acceptor_gain	1.0000
17:82756164:G:GG	acceptor_gain	1.0000
17:82766264:TAGGT:T	acceptor_loss	1.0000
17:82766265:AGGT:A	acceptor_loss	1.0000
17:82766366:GAA:G	donor_gain	1.0000
17:82766369:G:GG	donor_gain	1.0000
17:82768414:TTTTA:T	acceptor_loss	1.0000
17:82768415:TTTA:T	acceptor_loss	1.0000
17:82768416:TTA:T	acceptor_loss	1.0000
17:82768417:TAG:T	acceptor_loss	1.0000
17:82768418:AGGCT:A	acceptor_loss	1.0000
17:82768419:G:GC	acceptor_loss	1.0000
17:82768564:GAG:G	donor_gain	1.0000
17:82768566:GGT:G	donor_loss	1.0000
17:82768567:G:A	donor_loss	1.0000
17:82768568:T:G	donor_loss	1.0000
17:82772450:A:AG	acceptor_gain	1.0000
17:82772451:G:GG	acceptor_gain	1.0000
17:82781718:CCTGG:C	donor_loss	1.0000
17:82781719:CTGG:C	donor_loss	1.0000
17:82781720:TGGT:T	donor_loss	1.0000
17:82781721:GGT:G	donor_loss	1.0000
17:82781722:G:C	donor_loss	1.0000
17:82781722:G:GG	donor_gain	1.0000
17:82781723:T:A	donor_loss	1.0000
17:82797753:TTAG:T	acceptor_loss	1.0000
17:82797754:TAGGC:T	acceptor_loss	1.0000
17:82797755:A:AG	acceptor_gain	1.0000
17:82797756:G:A	acceptor_loss	1.0000

AlphaMissense

7779 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:82870319:T:A	W472R	0.998
17:82870319:T:C	W472R	0.998
17:82870321:G:C	W472C	0.998
17:82870321:G:T	W472C	0.998
17:82884189:G:C	R507T	0.998
17:82870296:G:T	R464M	0.997
17:82884190:A:C	R507S	0.997
17:82884190:A:T	R507S	0.997
17:82889681:A:T	E516V	0.997
17:82884189:G:T	R507I	0.996
17:82884198:C:A	A510D	0.996
17:82889672:C:A	A513D	0.996
17:82889682:G:C	E516D	0.996
17:82889682:G:T	E516D	0.996
17:82889693:G:C	R520T	0.996
17:82889694:A:C	R520S	0.996
17:82889694:A:T	R520S	0.996
17:82889679:G:C	Q515H	0.995
17:82889679:G:T	Q515H	0.995
17:82893599:T:A	V539D	0.995
17:82768477:T:C	F165L	0.994
17:82768479:T:A	F165L	0.994
17:82768479:T:G	F165L	0.994
17:82807662:C:A	A381D	0.994
17:82807667:G:C	G383R	0.994
17:82809713:G:A	G385D	0.994
17:82870296:G:C	R464T	0.994
17:82889669:C:A	A512D	0.994
17:82889671:G:C	A513P	0.994
17:82814878:T:C	L421P	0.993

dbSNP variants (sampled 300 via entrez): RS1000001025 (17:82897070 G>A,T), RS1000022488 (17:82845569 C>G), RS1000025769 (17:82881144 C>T), RS1000038308 (17:82834915 G>A), RS1000056132 (17:82800468 A>C,G), RS1000079491 (17:82801390 C>T), RS1000096183 (17:82932410 C>G,T), RS1000096452 (17:82816652 G>A,C), RS1000103685 (17:82865739 G>T), RS1000109587 (17:82760326 C>G), RS1000119656 (17:82819190 A>G), RS1000129005 (17:82915992 C>G,T), RS1000136288 (17:82866036 A>G), RS1000140332 (17:82817654 C>T), RS1000150059 (17:82779049 G>C)

Disease associations

OMIM: gene MIM:604649 | disease phenotypes: MIM:617193, MIM:610227, MIM:602082

GenCC curated gene-disease

Disease	Classification	Inheritance
early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	Definitive	AR

Mondo (4): early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (MONDO:0044646), seborrhea-like dermatitis with psoriasiform elements (MONDO:0012446), intellectual disability (MONDO:0001071), Thiel-Behnke corneal dystrophy (MONDO:0011185)

Orphanet (4): Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (Orphanet:496641), Seborrhea-like dermatitis with psoriasiform elements (Orphanet:168606), Thiel-Behnke corneal dystrophy (Orphanet:98960), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

87 total (30 of 87 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000400	Macrotia
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000582	Upslanted palpebral fissure
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000664	Synophrys
HP:0000687	Widely spaced teeth
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001298	Encephalopathy
HP:0001308	Tongue fasciculations

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002926_2	Bone mineral accretion in asthma (oral corticosteroid dose interaction)	3.000000e-08
GCST006988_104	Blond vs. brown/black hair color	8.000000e-11
GCST008179_5	Moderate-to-late spontaneous preterm birth	1.000000e-06
GCST008358_1	Response to cognitive-behavioural therapy in anxiety and major depressive disorders	2.000000e-06
GCST90002395_277	Mean platelet volume	6.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007591	bone mineral accretion measurement
EFO:0003924	hair color
EFO:0006917	spontaneous preterm birth
EFO:0007820	cognitive behavioural therapy

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C535942	Corneal dystrophy, Thiel-Behnke type (supp.)
C565217	Seborrhea-Like Dermatitis with Psoriasiform Elements (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066500 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.34	Kd	4.589	nM	CHEMBL3752910
8.34	ED50	4.589	nM	CHEMBL3752910
8.27	Kd	5.417	nM	CHEMBL5653589
8.27	ED50	5.417	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149554: Binding affinity to human TBCD incubated for 45 mins by Kinobead based pull down assay	kd	0.0046	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149554: Binding affinity to human TBCD incubated for 45 mins by Kinobead based pull down assay	kd	0.0054	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	5
bisphenol A	affects methylation, decreases expression, decreases methylation, affects cotreatment	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
bisphenol F	affects cotreatment, decreases methylation, decreases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
bisphenol S	increases expression, increases methylation	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Arsenic	affects methylation, increases abundance, increases expression	2
Ozone	increases expression, increases abundance, affects cotreatment	2
Aflatoxin B1	decreases methylation, affects expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
decabromobiphenyl ether	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652596	Binding	Binding affinity to human TBCD incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D3AD	GM28478	Transformed cell line	Male
CVCL_D3AE	GM28543	Transformed cell line	Male

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders