CCT4

Summary

CCT4 (chaperonin containing TCP1 subunit 4, HGNC:1617) is a protein-coding gene on chromosome 2p15, encoding T-complex protein 1 subunit delta (P50991). Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The chaperonin containing TCP1 (MIM 186980) complex (CCT), also called the TCP1 ring complex, consists of 2 back-to-back rings, each containing 8 unique but homologous subunits, such as CCT4. CCT assists the folding of newly translated polypeptide substrates through multiple rounds of ATP-driven release and rebinding of partially folded intermediate forms. Substrates of CCT include the cytoskeletal proteins actin (see MIM 102560) and tubulin (see MIM 191130), as well as alpha-transducin (MIM 139330) (Won et al., 1998 [PubMed 9819444]).

Source: NCBI Gene 10575 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 106 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_006430

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1617
Approved symbol	CCT4
Name	chaperonin containing TCP1 subunit 4
Location	2p15
Locus type	gene with protein product
Status	Approved
Aliases	Cctd
Ensembl gene	ENSG00000115484
Ensembl biotype	protein_coding
OMIM	605142
Entrez	10575

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 20 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000394440, ENST00000461370, ENST00000461540, ENST00000544079, ENST00000897687, ENST00000897688, ENST00000897689, ENST00000897690, ENST00000897691, ENST00000897692, ENST00000912678, ENST00000912679, ENST00000912680, ENST00000912681, ENST00000912682, ENST00000912683, ENST00000912684, ENST00000912685, ENST00000942384, ENST00000942385, ENST00000942386, ENST00000942387

RefSeq mRNA: 2 — MANE Select: NM_006430 NM_001256721, NM_006430

CCDS: CCDS33206, CCDS58711

Canonical transcript exons

ENST00000394440 — 14 exons

Exon	Start	End
ENSE00000757743	61880286	61880394
ENSE00000757746	61877393	61877514
ENSE00000757748	61876920	61877052
ENSE00000757752	61873197	61873293
ENSE00000757754	61873002	61873112
ENSE00000757756	61872458	61872588
ENSE00000757758	61872082	61872316
ENSE00001154232	61868085	61868706
ENSE00001518483	61888381	61888656
ENSE00003518514	61869440	61869553
ENSE00003526930	61885020	61885072
ENSE00003586214	61878869	61879011
ENSE00003616937	61883459	61883548
ENSE00003682126	61876095	61876234

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 197.2465 / max 972.7196, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28684	182.7754	1826
28683	6.9608	1614
28682	5.3673	1348
28681	1.4489	668
28680	0.6486	387
28679	0.0454	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.45	gold quality
ventricular zone	UBERON:0003053	98.84	gold quality
cortical plate	UBERON:0005343	98.78	gold quality
parotid gland	UBERON:0001831	98.72	gold quality
embryo	UBERON:0000922	98.66	gold quality
ganglionic eminence	UBERON:0004023	98.59	gold quality
cartilage tissue	UBERON:0002418	98.44	gold quality
mammary duct	UBERON:0001765	98.36	gold quality
adult organism	UBERON:0007023	98.34	gold quality
epithelium of nasopharynx	UBERON:0001951	98.31	gold quality
epithelium of mammary gland	UBERON:0003244	98.28	gold quality
mammalian vulva	UBERON:0000997	98.27	gold quality
tibialis anterior	UBERON:0001385	98.13	gold quality
germinal epithelium of ovary	UBERON:0001304	98.06	gold quality
esophagus squamous epithelium	UBERON:0006920	98.03	gold quality
deltoid	UBERON:0001476	97.99	gold quality
tibia	UBERON:0000979	97.96	gold quality
body of pancreas	UBERON:0001150	97.96	gold quality
skin of hip	UBERON:0001554	97.96	gold quality
tongue squamous epithelium	UBERON:0006919	97.96	gold quality
pons	UBERON:0000988	97.95	gold quality
nipple	UBERON:0002030	97.94	gold quality
upper leg skin	UBERON:0004262	97.91	gold quality
islet of Langerhans	UBERON:0000006	97.90	gold quality
pericardium	UBERON:0002407	97.90	gold quality
hair follicle	UBERON:0002073	97.85	gold quality
trabecular bone tissue	UBERON:0002483	97.85	gold quality
sperm	CL:0000019	97.84	gold quality
ovary	UBERON:0000992	97.83	gold quality
parietal pleura	UBERON:0002400	97.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting CCT4, 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-4425	100.00	67.59	1049
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-5094	98.63	67.11	1062
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-8086	97.21	64.13	331

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• Both CCT4 and CCT5 homo-oligomers have the property of forming 8-fold double rings absent the other subunits, and these complexes carry out chaperonin reactions without other partner subunits. (PMID:23612981)
• Chaperonin CCT is required for the correct folding of eIF3h and eIF3i subunits. (PMID:24320561)
• CCT4 suppression inhibits tumor growth in hepatocellular carcinoma by interacting with Cdc20. (PMID:34732665)
• CCT4 knockdown enhances the sensitivity of cisplatin by inhibiting glycolysis in human esophageal squamous cell carcinomas. (PMID:36102200)
• LINC01234 promoted malignant behaviors of breast cancer cells via hsa-miR-30c-2-3p/CCT4/mTOR signaling pathway. (PMID:38216268)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cct4	ENSDARG00000013475
mus_musculus	Cct4	ENSMUSG00000007739
rattus_norvegicus	Cct4	ENSRNOG00000009642
drosophila_melanogaster	CCT4	FBGN0032444
caenorhabditis_elegans		WBGENE00000379

Paralogs (13): PIKFYVE (ENSG00000115020), TCP1 (ENSG00000120438), MKKS (ENSG00000125863), CCT6B (ENSG00000132141), CCT7 (ENSG00000135624), HSPD1 (ENSG00000144381), CCT6A (ENSG00000146731), CCT5 (ENSG00000150753), CCT8 (ENSG00000156261), CCT3 (ENSG00000163468), CCT2 (ENSG00000166226), BBS12 (ENSG00000181004), CCT8L2 (ENSG00000198445)

Protein

Protein identifiers

T-complex protein 1 subunit delta — P50991 (reviewed: P50991)

Alternative names: CCT-delta, Chaperonin containing T-complex polypeptide 1 subunit 4, Stimulator of TAR RNA-binding

All UniProt accessions (1): P50991

UniProt curated annotations — full annotation on UniProt →

Function. Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis. The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance. As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia.

Subunit / interactions. Component of the chaperonin-containing T-complex (TRiC), a hexadecamer composed of two identical back-to-back stacked rings enclosing a protein folding chamber. Each ring is made up of eight different subunits: TCP1/CCT1, CCT2, CCT3, CCT4, CCT5, CCT6A/CCT6, CCT7, CCT8. Interacts with PACRG. Interacts with DNAAF4. Interacts with DLEC1.

Subcellular location. Cytoplasm. Melanosome. Cytoskeleton. Microtubule organizing center. Centrosome. Cilium basal body.

Disease relevance. De novo genetic variants in nearly every subunit of the TRiC complex, including CCT4, have been found in individuals with a broad spectrum of brain malformations, and clinical phenotypes ranging from mild to severe epilepsy, developmental delay, intellectual disability, ataxia, and other features of cerebral malfunction.

Similarity. Belongs to the TCP-1 chaperonin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P50991-1	1	yes
P50991-2	2

RefSeq proteins (2): NP_001243650, NP_006421* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002194	Chaperonin_TCP-1_CS	Conserved_site
IPR002423	Cpn60/GroEL/TCP-1	Family
IPR012717	Chap_CCT_delta	Family
IPR017998	TCP-1	Family
IPR027409	GroEL-like_apical_dom_sf	Homologous_superfamily
IPR027410	TCP-1-like_intermed_sf	Homologous_superfamily
IPR027413	GROEL-like_equatorial_sf	Homologous_superfamily
IPR053374
IPR054827	TCP-1-like	Family

Pfam: PF00118

Enzyme classification (BRENDA):

• EC 3.6.4.B10 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (88 total): strand 28, helix 22, binding site 15, modified residue 10, turn 6, sequence conflict 2, initiator methionine 1, chain 1, region of interest 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

66 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7NVL	ELECTRON MICROSCOPY	2.5
8SH9	ELECTRON MICROSCOPY	2.7
8SHE	ELECTRON MICROSCOPY	2.8
8SHG	ELECTRON MICROSCOPY	2.8
8SHN	ELECTRON MICROSCOPY	2.8
7TTT	ELECTRON MICROSCOPY	2.9
8SG9	ELECTRON MICROSCOPY	2.9
8SGC	ELECTRON MICROSCOPY	2.9
8SGL	ELECTRON MICROSCOPY	2.9
8SHD	ELECTRON MICROSCOPY	2.9
8SHQ	ELECTRON MICROSCOPY	2.9
9NOQ	ELECTRON MICROSCOPY	2.9
9NRH	ELECTRON MICROSCOPY	2.9
7NVN	ELECTRON MICROSCOPY	3
7TRG	ELECTRON MICROSCOPY	3
8SG8	ELECTRON MICROSCOPY	3
8SHA	ELECTRON MICROSCOPY	3
8SHF	ELECTRON MICROSCOPY	3
8SHL	ELECTRON MICROSCOPY	3
8SHO	ELECTRON MICROSCOPY	3
8SHP	ELECTRON MICROSCOPY	3
8SHT	ELECTRON MICROSCOPY	3
9NPW	ELECTRON MICROSCOPY	3
9NQ1	ELECTRON MICROSCOPY	3
9NRG	ELECTRON MICROSCOPY	3
7NVM	ELECTRON MICROSCOPY	3.1
7X0A	ELECTRON MICROSCOPY	3.1
7X0S	ELECTRON MICROSCOPY	3.1
8HKI	ELECTRON MICROSCOPY	3.1
8I9U	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50991-F1	90.05	0.77

Antibody-complex structures (SAbDab): 4 — 7NVL, 7NVM, 7NVN, 7NVO

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (15): 107; 108; 172; 173; 174; 174; 425; 510; 53; 53; 104; 105 …

Post-translational modifications (10): 19, 21, 36, 184, 202, 288, 302, 319, 326, 444

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-389957	Prefoldin mediated transfer of substrate to CCT/TriC
R-HSA-389960	Formation of tubulin folding intermediates by CCT/TriC
R-HSA-390450	Folding of actin by CCT/TriC
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-5620922	BBSome-mediated cargo-targeting to cilium
R-HSA-6814122	Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-389958	Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding
R-HSA-390466	Chaperonin-mediated protein folding
R-HSA-391251	Protein folding
R-HSA-392499	Metabolism of proteins
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane

MSigDB gene sets: 316 (showing top): GNF2_CKS1B, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_SINGLE_FERTILIZATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MATTIOLI_MGUS_VS_PCL, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, MORF_CDK2, HSIAO_HOUSEKEEPING_GENES, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN

GO Biological Process (7): protein folding (GO:0006457), binding of sperm to zona pellucida (GO:0007339), positive regulation of telomere maintenance via telomerase (GO:0032212), protein stabilization (GO:0050821), scaRNA localization to Cajal body (GO:0090666), positive regulation of protein localization to Cajal body (GO:1904871), positive regulation of telomerase RNA localization to Cajal body (GO:1904874)

GO Molecular Function (9): RNA binding (GO:0003723), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), protein folding chaperone (GO:0044183), obsolete unfolded protein binding (GO:0051082), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (12): zona pellucida receptor complex (GO:0002199), nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), chaperonin-containing T-complex (GO:0005832), microtubule (GO:0005874), melanosome (GO:0042470), cell body (GO:0044297), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	3
Chaperonin-mediated protein folding	3
Cargo trafficking to the periciliary membrane	1
Protein folding	1
Metabolism of proteins	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
ATP-dependent activity	2
cellular process	1
protein maturation	1
sperm-egg recognition	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
positive regulation of telomere maintenance via telomere lengthening	1
positive regulation of DNA biosynthetic process	1
regulation of protein stability	1
RNA localization to Cajal body	1
positive regulation of protein localization to nucleus	1
protein localization to Cajal body	1
regulation of protein localization to Cajal body	1
positive regulation of biological process	1
telomerase RNA localization to Cajal body	1
regulation of telomerase RNA localization to Cajal body	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
molecular_function	1
protein folding	1
protein folding chaperone	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
chaperonin-containing T-complex	1
protein-containing complex	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
cytoplasm	1
cytosol	1
protein folding chaperone complex	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
pigment granule	1
extracellular vesicle	1

Protein interactions and networks

STRING

4559 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCT4	CCT5	P48643	989
CCT4	CCT8	P50990	989
CCT4	CCT3	P49368	989
CCT4	CCT2	P78371	989
CCT4	CCT7	Q99832	988
CCT4	TCP1	P17987	980
CCT4	CCT6A	P40227	978
CCT4	TARBP1	Q13395	840
CCT4	CFAP52	Q8N1V2	830
CCT4	SCARB1	Q8WTV0	822
CCT4	SCARB2	Q14108	811
CCT4	CD36	P16671	792
CCT4	DCTN1	Q14203	752
CCT4	EEF1A1	P04719	662
CCT4	RBM8A	Q9Y5S9	635

IntAct

513 interactions, top by confidence:

A	B	Type	Score
IGBP1	PPP6C	psi-mi:“MI:0914”(association)	0.940
STK24	STK25	psi-mi:“MI:0914”(association)	0.890
STRN3	STK25	psi-mi:“MI:0914”(association)	0.880
CDK5	FIBP	psi-mi:“MI:0914”(association)	0.840
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
PPP2CA	STRN	psi-mi:“MI:0914”(association)	0.840
WRAP53	DKC1	psi-mi:“MI:0914”(association)	0.830
CCT2	CCT4	psi-mi:“MI:0915”(physical association)	0.810
CCT4	CCT2	psi-mi:“MI:0915”(physical association)	0.810
PPP2CB	STRN	psi-mi:“MI:0914”(association)	0.790
TUBG1	TUBG1	psi-mi:“MI:2364”(proximity)	0.760
PPP4C	TCP1	psi-mi:“MI:0914”(association)	0.730
STRN4	STRN	psi-mi:“MI:0914”(association)	0.730
TCP1	CCT4	psi-mi:“MI:0915”(physical association)	0.670
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
TUBA1B	TXNDC9	psi-mi:“MI:0914”(association)	0.640
ACTR3	ARPC2	psi-mi:“MI:0914”(association)	0.640
HDAC11	CLUH	psi-mi:“MI:0914”(association)	0.640
PPP2R2C	TCP1	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
PPP2R2D	ENSA	psi-mi:“MI:2364”(proximity)	0.570
Cdc20	BUB1	psi-mi:“MI:0914”(association)	0.560
CCT4	CCNH	psi-mi:“MI:0915”(physical association)	0.560
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
IRAK1	SEC16A	psi-mi:“MI:0914”(association)	0.530
PTK6	TCP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (831): CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT4 (Affinity Capture-MS)

ESM2 similar proteins: A8X6I9, O00782, O15891, O77622, O94501, P11983, P12612, P12613, P17987, P18279, P28480, P28769, P39077, P40227, P41988, P42943, P47079, P50991, P54408, P54409, P54410, P78921, P80313, P80317, P87153, Q2NKZ1, Q32L40, Q3MHL7, Q3T084, Q4R5G2, Q54ER7, Q54TH8, Q552J0, Q5R5C8, Q5R637, Q5RCD2, Q5ZJ54, Q5ZJK8, Q61390, Q7TPB1

Diamond homologs: O00782, O04450, O15891, O24730, O24731, O24732, O24734, O24735, O26320, O26885, O28045, O28821, O30560, O30561, O57762, O74341, O93624, P12613, P17987, P18279, P28480, P28488, P28769, P39077, P40412, P40413, P41988, P42943, P46219, P47208, P47209, P48424, P48425, P48605, P48643, P49368, P50016, P50143, P50991, P50999

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CCT4	“form complex”	TRiC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 247 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
Formation of tubulin folding intermediates by CCT/TriC	10	25.6×	8e-10
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	10	24.7×	8e-10
Prefoldin mediated transfer of substrate to CCT/TriC	10	23.9×	9e-10
Chaperonin-mediated protein folding	11	20.0×	8e-10
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	6	19.8×	1e-05
Transport of connexons to the plasma membrane	6	19.8×	1e-05
Protein folding	11	17.3×	3e-09
Gap junction trafficking and regulation	6	17.3×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance via telomerase	7	25.3×	3e-06
chaperone-mediated protein complex assembly	5	17.3×	9e-04
mitotic cell cycle	17	11.2×	3e-10
mitotic spindle organization	8	10.7×	9e-05
rhythmic process	7	8.7×	2e-03
microtubule cytoskeleton organization	14	8.4×	1e-06
protein folding	12	6.1×	9e-05
MAPK cascade	8	6.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1373 predictions. Top by Δscore:

Variant	Effect	Δscore
2:61869433:CACTT:C	donor_loss	1.0000
2:61869434:ACTTA:A	donor_loss	1.0000
2:61869437:TA:T	donor_loss	1.0000
2:61869438:A:AC	donor_gain	1.0000
2:61869438:AC:A	donor_gain	1.0000
2:61869439:C:CC	donor_gain	1.0000
2:61869439:C:CG	donor_loss	1.0000
2:61869439:CC:C	donor_gain	1.0000
2:61869439:CCA:C	donor_gain	1.0000
2:61869439:CCACA:C	donor_gain	1.0000
2:61869549:CCACC:C	acceptor_gain	1.0000
2:61869550:CACC:C	acceptor_gain	1.0000
2:61869550:CACCC:C	acceptor_gain	1.0000
2:61869551:ACC:A	acceptor_gain	1.0000
2:61869552:CC:C	acceptor_gain	1.0000
2:61869552:CCC:C	acceptor_gain	1.0000
2:61869553:CC:C	acceptor_gain	1.0000
2:61869553:CCTG:C	acceptor_loss	1.0000
2:61869554:C:CC	acceptor_gain	1.0000
2:61869555:T:A	acceptor_loss	1.0000
2:61869562:C:CT	acceptor_gain	1.0000
2:61872079:TA:T	donor_loss	1.0000
2:61872080:A:AC	donor_gain	1.0000
2:61872080:A:C	donor_loss	1.0000
2:61872081:C:CC	donor_gain	1.0000
2:61872081:C:CG	donor_loss	1.0000
2:61872081:CCTTT:C	donor_gain	1.0000
2:61872094:AATG:A	donor_gain	1.0000
2:61872113:C:CA	donor_gain	1.0000
2:61872312:GAGCC:G	acceptor_gain	1.0000

AlphaMissense

3494 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:61869450:A:T	I532K	1.000
2:61872134:A:G	L480P	1.000
2:61872176:G:T	A466D	1.000
2:61872177:C:G	A466P	1.000
2:61872492:C:G	A408P	1.000
2:61872493:A:C	D407E	1.000
2:61872493:A:T	D407E	1.000
2:61872494:T:A	D407V	1.000
2:61872494:T:C	D407G	1.000
2:61872494:T:G	D407A	1.000
2:61872506:C:G	R403P	1.000
2:61872513:C:G	A401P	1.000
2:61878869:C:A	K174N	1.000
2:61878869:C:G	K174N	1.000
2:61880351:C:T	G105D	1.000
2:61880353:A:C	D104E	1.000
2:61880353:A:T	D104E	1.000
2:61880354:T:A	D104V	1.000
2:61880354:T:G	D104A	1.000
2:61880355:C:G	D104H	1.000
2:61880357:C:T	G103E	1.000
2:61883466:G:T	A88D	1.000
2:61883496:A:G	L78P	1.000
2:61883508:C:T	G74D	1.000
2:61883509:C:G	G74R	1.000
2:61883510:A:C	D73E	1.000
2:61883510:A:T	D73E	1.000
2:61883511:T:A	D73V	1.000
2:61883511:T:C	D73G	1.000
2:61883511:T:G	D73A	1.000

dbSNP variants (sampled 300 via entrez): RS1000014408 (2:61876573 C>T), RS1000021224 (2:61880978 G>A), RS1000023325 (2:61885955 A>C,G), RS1000070995 (2:61882805 C>T), RS1000089758 (2:61886663 C>G), RS1000096297 (2:61870493 C>T), RS1000218550 (2:61867729 AAAAAAAT>A), RS1000294081 (2:61877526 A>C,G,T), RS1000631263 (2:61890447 G>A), RS1000764070 (2:61874303 A>C,G), RS1000824078 (2:61868742 A>G), RS1000941535 (2:61869181 A>G), RS1001092513 (2:61882194 A>C), RS1001290707 (2:61870965 C>T), RS1001311402 (2:61888612 T>C)

Disease associations

OMIM: gene MIM:605142 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (2): neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006956_8	Erectile dysfunction	8.000000e-06
GCST007385_31	Plasma free amino acid levels	2.000000e-08
GCST007385_9	Plasma free amino acid levels	6.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005134	amino acid measurement
EFO:0009775	threonine measurement
EFO:0009771	methionine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725077 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.79	Kd	1629	nM	CHEMBL3752910
5.79	ED50	1629	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 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	2148022: Binding affinity to human CCT4 incubated for 45 mins by Kinobead based pull down assay	kd	1.6287	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, decreases methylation	3
Tobacco Smoke Pollution	increases expression, affects expression	3
Valproic Acid	affects expression, decreases expression, decreases methylation	3
bisphenol F	affects cotreatment, decreases expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	increases methylation, increases expression	2
Cyclosporine	increases expression	2
beta-N-methylamino-L-alanine	increases expression	1
triphenyl phosphate	affects expression	1
titanium dioxide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, increases reaction	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
indirubin	decreases expression	1
dinophysistoxin 1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants, Occupational	affects expression	1
Aminoglutethimide	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Caffeine	affects phosphorylation	1
Cannabidiol	decreases expression, affects cotreatment	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651064	Binding	Binding affinity to human CCT4 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice