CCT5

Summary

CCT5 (chaperonin containing TCP1 subunit 5, HGNC:1618) is a protein-coding gene on chromosome 5p15.2, encoding T-complex protein 1 subunit epsilon (P48643). 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 99.7% of cancer cell lines).

The protein encoded by this gene is a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). This complex consists of two identical stacked rings, each containing eight different proteins. Unfolded polypeptides enter the central cavity of the complex and are folded in an ATP-dependent manner. The complex folds various proteins, including actin and tubulin. Mutations in this gene cause hereditary sensory and autonomic neuropathy with spastic paraplegia (HSNSP). Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 5 and 13.

Source: NCBI Gene 22948 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary sensory and autonomic neuropathy with spastic paraplegia (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 404 total — 1 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_012073

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1618
Approved symbol	CCT5
Name	chaperonin containing TCP1 subunit 5
Location	5p15.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0098, CCTE
Ensembl gene	ENSG00000150753
Ensembl biotype	protein_coding
OMIM	610150
Entrez	22948

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 31 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay

ENST00000280326, ENST00000423695, ENST00000503026, ENST00000503454, ENST00000506600, ENST00000508451, ENST00000509846, ENST00000510326, ENST00000511700, ENST00000511995, ENST00000512975, ENST00000514674, ENST00000515390, ENST00000515676, ENST00000625723, ENST00000882451, ENST00000882452, ENST00000882453, ENST00000882454, ENST00000882455, ENST00000882456, ENST00000882457, ENST00000938094, ENST00000938095, ENST00000938096, ENST00000938097, ENST00000938098, ENST00000938099, ENST00000938100, ENST00000938101, ENST00000938102, ENST00000938103, ENST00000938104, ENST00000938105, ENST00000938106, ENST00000938107, ENST00000938108, ENST00000964554, ENST00000964555, ENST00000964556

RefSeq mRNA: 5 — MANE Select: NM_012073 NM_001306153, NM_001306154, NM_001306155, NM_001306156, NM_012073

CCDS: CCDS3877, CCDS77996, CCDS82988, CCDS82989, CCDS82990

Canonical transcript exons

ENST00000280326 — 11 exons

Exon	Start	End
ENSE00000996132	10254674	10254838
ENSE00001082659	10261560	10261745
ENSE00001082663	10262481	10262618
ENSE00001266466	10264656	10266389
ENSE00002069217	10250280	10250445
ENSE00003482029	10255955	10256153
ENSE00003540511	10258111	10258303
ENSE00003551017	10254145	10254205
ENSE00003610378	10263134	10263314
ENSE00003685447	10258386	10258535
ENSE00003688865	10260792	10260911

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 134.6304 / max 2880.7734, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55688	124.9908	1822
55686	6.1450	1589
55687	3.4946	1400

Top tissues by expression

300 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	99.35	gold quality
endometrium epithelium	UBERON:0004811	99.18	gold quality
adrenal tissue	UBERON:0018303	98.94	gold quality
ventricular zone	UBERON:0003053	98.88	gold quality
embryo	UBERON:0000922	98.83	gold quality
ganglionic eminence	UBERON:0004023	98.79	gold quality
monocyte	CL:0000576	98.46	gold quality
mononuclear cell	CL:0000842	98.44	gold quality
rectum	UBERON:0001052	98.40	gold quality
smooth muscle tissue	UBERON:0001135	98.40	gold quality
leukocyte	CL:0000738	98.39	gold quality
right testis	UBERON:0004534	98.39	gold quality
cortical plate	UBERON:0005343	98.32	gold quality
islet of Langerhans	UBERON:0000006	98.30	gold quality
left testis	UBERON:0004533	98.27	gold quality
stromal cell of endometrium	CL:0002255	98.04	gold quality
testis	UBERON:0000473	97.97	gold quality
mucosa of transverse colon	UBERON:0004991	97.90	gold quality
vermiform appendix	UBERON:0001154	97.82	gold quality
right adrenal gland	UBERON:0001233	97.78	gold quality
left adrenal gland	UBERON:0001234	97.77	gold quality
esophagus mucosa	UBERON:0002469	97.76	gold quality
peritoneum	UBERON:0002358	97.69	gold quality
omental fat pad	UBERON:0010414	97.69	gold quality
left adrenal gland cortex	UBERON:0035825	97.69	gold quality
adrenal gland	UBERON:0002369	97.64	gold quality
caecum	UBERON:0001153	97.55	gold quality
right adrenal gland cortex	UBERON:0035827	97.55	gold quality
lymph node	UBERON:0000029	97.54	gold quality
olfactory bulb	UBERON:0002264	97.52	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	26.94
E-MTAB-9067	yes	21.43
E-HCAD-13	yes	19.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

58 targeting CCT5, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-7152-5P	99.60	69.33	2094

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 11)

• A missense mutation within the CCT5 gene is associated with autosomal recessive mutilating sensory neuropathy with spastic paraplegia. (PMID:16399879)
• mRNA expression of CCT5, RGS3, and YKT6 was significantly up-regulated in p53-mutated tumors and associated with a low response rate to docetaxel. (PMID:16821082)
• introduction of the truncated human CCT epsilon subunit into yeast cells (PMID:22232265)
• 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)
• H147R CCT5 was not as efficient in chaperoning these substrates as wild type CCT5. (PMID:25124038)
• CCT5 complex caps mutant mHTT fibrils at their tips and encapsulates mHTT oligomers, providing a structural description of the inhibition of mHTTQ46-Ex1 by CCT5 complex and a shared mechanism of mHTT inhibition between TRiC chaperonin and the CCT5 complex (PMID:25995452)
• A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy. (PMID:33076433)
• CCT5 interacts with cyclin D1 promoting lung adenocarcinoma cell migration and invasion. (PMID:34217974)
• CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/beta-catenin signalling pathway. (PMID:35194191)
• Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies. (PMID:36768350)
• Increased CCT5 expression is a potential unfavourable factor promoting the growth of nasopharyngeal carcinoma. (PMID:39286844)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cct5	ENSDARG00000045399
mus_musculus	Cct5	ENSMUSG00000022234
rattus_norvegicus	Cct5	ENSRNOG00000011632
drosophila_melanogaster	CCT5	FBGN0010621
caenorhabditis_elegans		WBGENE00000380

Paralogs (13): PIKFYVE (ENSG00000115020), CCT4 (ENSG00000115484), TCP1 (ENSG00000120438), MKKS (ENSG00000125863), CCT6B (ENSG00000132141), CCT7 (ENSG00000135624), HSPD1 (ENSG00000144381), CCT6A (ENSG00000146731), CCT8 (ENSG00000156261), CCT3 (ENSG00000163468), CCT2 (ENSG00000166226), BBS12 (ENSG00000181004), CCT8L2 (ENSG00000198445)

Protein

Protein identifiers

T-complex protein 1 subunit epsilon — P48643 (reviewed: P48643)

Alternative names: CCT-epsilon, Chaperonin containing T-complex polypeptide 1 subunit 5

All UniProt accessions (8): P48643, B7ZAR1, D6RIZ7, E7ENZ3, E9PCA1, H0Y914, H0Y958, V9HW37

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. Interacts with SPMAP2.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Ubiquitinated by the DCX(DCAF12) complex specifically recognizes the diglutamate (Glu-Glu) at the C-terminus, leading to its degradation.

Disease relevance. Neuropathy, hereditary sensory, with spastic paraplegia, autosomal recessive (HSNSP) [MIM:256840] A disease characterized by spastic paraplegia and progressive distal sensory neuropathy leading to mutilating ulcerations of the upper and lower limbs. The disease is caused by variants affecting the gene represented in this entry. De novo genetic variants in nearly every subunit of the TRiC complex, including CCT5, 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.

Induction. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).

Similarity. Belongs to the TCP-1 chaperonin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P48643-1	1	yes
P48643-2	2

RefSeq proteins (5): NP_001293082, NP_001293083, NP_001293084, NP_001293085, NP_036205* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002194	Chaperonin_TCP-1_CS	Conserved_site
IPR002423	Cpn60/GroEL/TCP-1	Family
IPR012718	Chap_CCT_epsi	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 (85 total): strand 24, helix 23, binding site 14, cross-link 7, modified residue 4, turn 4, sequence variant 3, splice variant 2, sequence conflict 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

69 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
8AJM	ELECTRON MICROSCOPY	2.83
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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48643-F1	89.34	0.62

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 (14): 175; 422; 422; 492; 508; 513; 53; 53; 104; 105; 106; 106 …

Post-translational modifications (11): 2, 26, 346, 539, 20, 210, 214, 265, 275, 279, 392

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: 371 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_SINGLE_FERTILIZATION, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, MORF_ESPL1, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, MORF_BUB1, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_RRM1, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION

GO Biological Process (7): protein folding (GO:0006457), binding of sperm to zona pellucida (GO:0007339), response to virus (GO:0009615), positive regulation of telomere maintenance via telomerase (GO:0032212), protein stabilization (GO:0050821), positive regulation of protein localization to Cajal body (GO:1904871), positive regulation of telomerase RNA localization to Cajal body (GO:1904874)

GO Molecular Function (12): mRNA 3’-UTR binding (GO:0003730), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), G-protein beta-subunit binding (GO:0031681), protein folding chaperone (GO:0044183), mRNA 5’-UTR binding (GO:0048027), beta-tubulin binding (GO:0048487), 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 (8): centrosome (GO:0005813), cytosol (GO:0005829), chaperonin-containing T-complex (GO:0005832), microtubule (GO:0005874), cell body (GO:0044297), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

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	3
mRNA binding	2
ATP-dependent activity	2
cellular process	1
protein maturation	1
sperm-egg recognition	1
response to other organism	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
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
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
molecular_function	1
protein folding	1
tubulin binding	1
protein folding chaperone	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
centriole	1
microtubule organizing center	1
cytoplasm	1
cytosol	1
protein folding chaperone complex	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCT5	CCT4	P50991	989
CCT5	CCT7	Q99832	988
CCT5	CCT3	P49368	988
CCT5	CCT2	P78371	988
CCT5	CCT8	P50990	980
CCT5	CCT6A	P40227	974
CCT5	SPMAP2	Q9P2T0	952
CCT5	TCP1	P17987	929
CCT5	CCT6B	Q92526	748
CCT5	HSPA8	P11142	701
CCT5	ATPSCKMT	Q6P4H8	674
CCT5	HSP90AA1	P07900	652
CCT5	HSP90AB1	P08238	649
CCT5	DNAJA1	P31689	628
CCT5	ACLY	P53396	608

IntAct

570 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
PPP2CB	STRN	psi-mi:“MI:0914”(association)	0.790
CCT5	CCT2	psi-mi:“MI:0915”(physical association)	0.740
TCP1	CCT5	psi-mi:“MI:0915”(physical association)	0.740
ZNRD2	CCT5	psi-mi:“MI:0915”(physical association)	0.740
PPP4C	TCP1	psi-mi:“MI:0914”(association)	0.730
STRN4	STRN	psi-mi:“MI:0914”(association)	0.730
MOB4	STK25	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
PPP2R2C	TCP1	psi-mi:“MI:0914”(association)	0.640
CTTNBP2	STK25	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
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
IRAK1	SEC16A	psi-mi:“MI:0914”(association)	0.530
TSSK6	TCP1	psi-mi:“MI:0914”(association)	0.530
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530

BioGRID (844): CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Two-hybrid), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT5 (Affinity Capture-MS)

ESM2 similar proteins: A0Q7J6, A1SYD3, A4FWX4, A4IWY2, A5UJM2, A5ULG4, A6UUN0, A6VGE3, A7NCH8, A9AAB0, B0TY16, B1H0I0, B2A5S2, B2SFU3, B2TPG6, B2UXF7, O04450, O26320, O26899, O27477, P39078, P40412, P40413, P47209, P48643, P54411, P61986, P61988, P80316, Q04NF4, Q04WN5, Q0BLP7, Q12TG0, Q12Z15, Q12Z64, Q14GM4, Q2A374, Q2NGN3, Q2NHX5, Q46LE0

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
CCT5	“form complex”	TRiC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 243 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
Prefoldin mediated transfer of substrate to CCT/TriC	10	26.4×	2e-09
Formation of tubulin folding intermediates by CCT/TriC	9	25.6×	1e-08
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	9	24.6×	1e-08
Chaperonin-mediated protein folding	10	20.2×	1e-08
Association of TriC/CCT with target proteins during biosynthesis	9	17.7×	2e-07
Protein folding	10	17.4×	3e-08
RHOBTB2 GTPase cycle	5	16.0×	4e-04
Cargo trafficking to the periciliary membrane	8	13.3×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance via telomerase	8	30.7×	8e-08
chaperone-mediated protein complex assembly	5	18.4×	7e-04
positive regulation of type I interferon production	6	13.2×	6e-04
mitotic cell cycle	14	9.8×	8e-08
mitotic spindle organization	6	8.5×	6e-03
microtubule cytoskeleton organization	12	7.6×	1e-05
protein folding	13	7.0×	1e-05
protein stabilization	15	5.2×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	196
Likely benign	105
Benign	66

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1802575	NM_012073.5(CCT5):c.670C>G (p.Leu224Val)	Likely pathogenic

SpliceAI

1611 predictions. Top by Δscore:

Variant	Effect	Δscore
5:10250441:TCAAG:T	donor_loss	1.0000
5:10250442:CAAGG:C	donor_loss	1.0000
5:10250443:AAGGT:A	donor_loss	1.0000
5:10250445:GGTAA:G	donor_loss	1.0000
5:10250446:GTAAT:G	donor_loss	1.0000
5:10254140:A:AG	acceptor_gain	1.0000
5:10254141:T:G	acceptor_gain	1.0000
5:10254143:A:AG	acceptor_gain	1.0000
5:10254144:G:GA	acceptor_gain	1.0000
5:10254144:GT:G	acceptor_gain	1.0000
5:10254144:GTCTC:G	acceptor_gain	1.0000
5:10254672:A:AG	acceptor_gain	1.0000
5:10254672:AG:A	acceptor_gain	1.0000
5:10254672:AGG:A	acceptor_gain	1.0000
5:10254673:G:GA	acceptor_gain	1.0000
5:10254673:GG:G	acceptor_gain	1.0000
5:10254673:GGG:G	acceptor_gain	1.0000
5:10254673:GGGC:G	acceptor_gain	1.0000
5:10254673:GGGCT:G	acceptor_gain	1.0000
5:10254835:GTTG:G	donor_gain	1.0000
5:10254837:TGGTA:T	donor_loss	1.0000
5:10254839:G:GG	donor_gain	1.0000
5:10254839:GTAAG:G	donor_loss	1.0000
5:10254840:T:G	donor_loss	1.0000
5:10255930:T:A	acceptor_gain	1.0000
5:10255950:TGCA:T	acceptor_loss	1.0000
5:10255951:GCAGT:G	acceptor_loss	1.0000
5:10255952:CA:C	acceptor_loss	1.0000
5:10255953:A:AG	acceptor_gain	1.0000
5:10255953:A:AT	acceptor_loss	1.0000

AlphaMissense

3596 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:10254196:G:A	G53R	1.000
5:10254196:G:C	G53R	1.000
5:10254197:G:A	G53E	1.000
5:10254205:G:T	G56W	1.000
5:10254674:G:A	G56E	1.000
5:10254724:G:C	D73H	1.000
5:10254725:A:C	D73A	1.000
5:10254725:A:G	D73G	1.000
5:10254725:A:T	D73V	1.000
5:10254726:T:A	D73E	1.000
5:10254726:T:G	D73E	1.000
5:10254727:G:T	G74W	1.000
5:10254728:G:A	G74E	1.000
5:10254815:G:A	G103E	1.000
5:10254815:G:T	G103V	1.000
5:10254817:G:C	D104H	1.000
5:10254818:A:C	D104A	1.000
5:10254818:A:T	D104V	1.000
5:10254819:T:A	D104E	1.000
5:10254819:T:G	D104E	1.000
5:10254821:G:A	G105E	1.000
5:10255981:G:C	A120P	1.000
5:10256150:A:T	K176I	1.000
5:10256151:A:C	K176N	1.000
5:10256151:A:T	K176N	1.000
5:10260824:T:G	C302W	1.000
5:10260828:T:A	W304R	1.000
5:10260828:T:C	W304R	1.000
5:10260830:G:C	W304C	1.000
5:10260830:G:T	W304C	1.000

dbSNP variants (sampled 300 via entrez): RS1000151223 (5:10258759 G>T), RS1000196897 (5:10262640 A>G,T), RS1000430343 (5:10248141 T>C), RS1000598991 (5:10261233 C>T), RS1000627240 (5:10266908 T>A), RS1000656833 (5:10256450 C>G,T), RS1000693552 (5:10253037 C>G), RS1000824841 (5:10257326 A>G), RS1000930198 (5:10261437 A>G), RS1001105854 (5:10257604 C>T), RS1001158206 (5:10257307 G>A), RS1001272696 (5:10257023 T>A), RS1001289890 (5:10258045 A>C,G), RS1001386227 (5:10262828 C>T), RS1001807827 (5:10266245 C>A)

Disease associations

OMIM: gene MIM:610150 | disease phenotypes: MIM:256840, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy with spastic paraplegia	Supportive	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (3): hereditary sensory and autonomic neuropathy with spastic paraplegia (MONDO:0009748), hereditary spastic paraplegia (MONDO:0019064), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Mutilating hereditary sensory neuropathy with spastic paraplegia (Orphanet:139578), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001760	Abnormal foot morphology
HP:0001886	Foot osteomyelitis
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002143	Abnormal spinal cord morphology
HP:0002169	Clonus
HP:0002936	Distal sensory impairment
HP:0003390	Sensory axonal neuropathy
HP:0003409	Distal sensory impairment of all modalities
HP:0003431	Decreased motor nerve conduction velocity
HP:0003477	Peripheral axonal neuropathy
HP:0003487	Babinski sign
HP:0003693	Distal amyotrophy
HP:0006121	Acral ulceration
HP:0006827	Atrophy of the spinal cord
HP:0007020	Progressive spastic paraplegia
HP:0007078	Decreased amplitude of sensory action potentials
HP:0007328	Impaired pain sensation
HP:0009830	Peripheral neuropathy
HP:0011463	Childhood onset
HP:0012153	Hypotriglyceridemia
HP:0012332	Abnormal autonomic nervous system physiology
HP:0034075	Decreased circulating apolipoprotein B concentration
HP:0200042	Skin ulcer

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001668_1	Pain	5.000000e-07
GCST009391_1144	Metabolite levels	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010457	Alpha ketoglutarate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C564948	Neuropathy, Hereditary Sensory, with Spastic Paraplegia, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295766 (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
9.67	Kd	0.216	nM	CHEMBL3752910
9.67	ED50	0.216	nM	CHEMBL3752910
7.29	Kd	51.64	nM	CHEMBL5653589
7.29	ED50	51.64	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 6 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	2148023: Binding affinity to human CCT5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0002	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148023: Binding affinity to human CCT5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0516	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol A	decreases expression	2
sodium arsenite	decreases expression	2
Silicon Dioxide	affects secretion, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	increases expression	1
arsenite	increases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases reaction, increases expression	1
bathocuproine sulfonate	affects cotreatment, decreases reaction, increases expression	1
lead chloride	decreases expression	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
JP8 aviation fuel	decreases expression	1
enniatins	affects cotreatment, increases expression	1
K 7174	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetylglucosamine	decreases expression	1
Air Pollutants, Occupational	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118578	Binding	Binding affinity to CCT5 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies