CLPB

Summary

CLPB (ClpB family mitochondrial disaggregase, HGNC:30664) is a protein-coding gene on chromosome 11q13.4, encoding Mitochondrial disaggregase (Q9H078). Functions as a regulatory ATPase and participates in secretion/protein trafficking process. It is a selective cancer dependency (DepMap: 10.8% of cell lines).

This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 81570 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-methylglutaconic aciduria, type VIIB (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 886 total — 35 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 121
• Cancer dependency (DepMap): dependent in 10.8% of screened cell lines
• MANE Select transcript: NM_001258392

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30664
Approved symbol	CLPB
Name	ClpB family mitochondrial disaggregase
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	SKD3, FLJ13152, ANKCLP
Ensembl gene	ENSG00000162129
Ensembl biotype	protein_coding
OMIM	616254
Entrez	81570

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 19 protein_coding, 5 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 3 retained_intron

ENST00000294053, ENST00000340729, ENST00000445069, ENST00000535477, ENST00000535990, ENST00000536297, ENST00000538021, ENST00000538039, ENST00000539148, ENST00000542555, ENST00000543042, ENST00000544382, ENST00000544683, ENST00000642187, ENST00000642288, ENST00000645105, ENST00000645650, ENST00000646117, ENST00000646359, ENST00000695924, ENST00000695925, ENST00000695926, ENST00000866362, ENST00000866363, ENST00000866364, ENST00000938927, ENST00000955683, ENST00000955684, ENST00000955685, ENST00000955686, ENST00000955687, ENST00000955688

RefSeq mRNA: 4 — MANE Select: NM_001258392 NM_001258392, NM_001258393, NM_001258394, NM_030813

CCDS: CCDS58153, CCDS58154, CCDS8215

Canonical transcript exons

ENST00000538039 — 16 exons

Exon	Start	End
ENSE00001062814	72329707	72329804
ENSE00001062819	72294620	72294693
ENSE00001062821	72295492	72295648
ENSE00001062826	72302304	72302348
ENSE00001062827	72301803	72301964
ENSE00001062830	72308527	72308604
ENSE00001093272	72317106	72317220
ENSE00002302745	72434072	72434531
ENSE00003489564	72380281	72380384
ENSE00003522845	72358880	72359008
ENSE00003538208	72294022	72294126
ENSE00003539650	72402966	72403052
ENSE00003573145	72307199	72307254
ENSE00003655323	72294325	72294444
ENSE00003659900	72430312	72430363
ENSE00003823175	72285495	72293615

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1793 / max 228.2490, expressed in 1811 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121160	16.9195	1811
121161	0.1644	17
121158	0.0550	13
121162	0.0281	4
121159	0.0123	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.47	gold quality
left testis	UBERON:0004533	98.96	gold quality
right testis	UBERON:0004534	98.81	gold quality
male germ cell	CL:0000015	98.11	gold quality
testis	UBERON:0000473	95.18	gold quality
adult organism	UBERON:0007023	93.89	gold quality
adrenal tissue	UBERON:0018303	88.80	gold quality
right adrenal gland	UBERON:0001233	86.45	gold quality
islet of Langerhans	UBERON:0000006	86.29	gold quality
right lobe of liver	UBERON:0001114	86.25	gold quality
stromal cell of endometrium	CL:0002255	86.16	gold quality
right adrenal gland cortex	UBERON:0035827	85.94	gold quality
left adrenal gland	UBERON:0001234	85.10	gold quality
monocyte	CL:0000576	84.53	gold quality
adrenal gland	UBERON:0002369	84.43	gold quality
mononuclear cell	CL:0000842	84.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.12	gold quality
leukocyte	CL:0000738	84.07	gold quality
left adrenal gland cortex	UBERON:0035825	83.97	gold quality
sural nerve	UBERON:0015488	83.91	gold quality
gastrocnemius	UBERON:0001388	83.22	gold quality
muscle of leg	UBERON:0001383	82.98	gold quality
adrenal cortex	UBERON:0001235	82.41	gold quality
liver	UBERON:0002107	82.39	gold quality
prefrontal cortex	UBERON:0000451	82.38	gold quality
pancreas	UBERON:0001264	81.90	gold quality
calcaneal tendon	UBERON:0003701	81.84	gold quality
cortical plate	UBERON:0005343	81.74	gold quality
body of pancreas	UBERON:0001150	81.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.52	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	32.84
E-ANND-3	yes	5.30
E-MTAB-8060	no	82.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting CLPB, 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-1252-5P	100.00	69.80	2774
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-6831-3P	97.49	69.29	505
HSA-MIR-4771	97.43	67.69	596

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 16)

• ClpB-DnaK reactivated all aggregated fusion proteins with similar efficiency, without unfolding native domains, demonstrating that partial threading of the misfolded moiety is sufficient to solubilize aggregates. (PMID:18488042)
• formation of the DnaK-ClpB bichaperone network is a three step process (PMID:19698713)
• ClpB can passively thread soluble denatured proteins. (PMID:25288401)
• Case Reports: bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation. (PMID:25595726)
• Mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria. (PMID:25597510)
• CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation. (PMID:25597511)
• Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria (PMID:25650066)
• The neonatal presentation of CLPB deficiency predicts the course of disease in later life, which is extremely important for counselling. (PMID:28687938)
• It present for the first time the biochemical characteristics of the human CLPB protein with the aim of shedding light on its physiological function and the pathogenesis of MEGCANN syndrome. (PMID:31917998)
• Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations. (PMID:32573439)
• Human CLPB forms ATP-dependent complexes in the mitochondrial intermembrane space. (PMID:32866687)
• Heterozygous variants of CLPB are a cause of severe congenital neutropenia. (PMID:34115842)
• Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency. (PMID:34140661)
• Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights. (PMID:36074910)
• Comprehensive structural characterization of the human AAA+ disaggregase CLPB in the apo- and substrate-bound states reveals a unique mode of action driven by oligomerization. (PMID:36745679)
• CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex. (PMID:38270563)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	CLPB	ENSDARG00000088463
mus_musculus	Clpb	ENSMUSG00000001829
rattus_norvegicus	Clpb	ENSRNOG00000019693

Protein

Protein identifiers

Mitochondrial disaggregase — Q9H078 (reviewed: Q9H078)

Alternative names: Suppressor of potassium transport defect 3

All UniProt accessions (13): A0A140VK11, A0A2R8Y602, A0A2R8Y6R5, A0A2R8Y7E8, A0A2R8YDH5, A0A2U3TZY2, Q9H078, F5GX99, F5H392, F5H7A5, F6SS08, H0YG50, H0YGM0

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins. Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6. Plays a role in granulocyte differentiation.

Subunit / interactions. Homododecamer when substrate-bound; the homododecamer consists of 2 homohexamers stacked head-to-head via ANK repeat-mediated interactions. The active substrate-bound form is likely to exist in a dynamic equilibrium between homohexamers and homododecamers. Homotetradecamer in the unbound state which is remodeled upon substrate binding into the homododecamer. Interacts with PHB and PHB2. Interacts with MAVS; the interaction is enhanced by Sendai virus infection.

Subcellular location. Mitochondrion intermembrane space.

Tissue specificity. Widely expressed (at protein level). Expressed in fetal, as well as in adult tissues, with highest levels in adult brain, including thalamus, hippocampus, occipital cortex and parietal cortex. Low expression in granulocytes.

Post-translational modifications. Proteolytically cleaved by protease PARL. ATP-dependent protein disaggregase activity is stimulated by PARL-mediated cleavage of the N-terminal autoinhibitory peptide.

Disease relevance. 3-methylglutaconic aciduria 7B (MGCA7B) [MIM:616271] An autosomal recessive inborn error of metabolism with a highly variable phenotype. Primary disease symptoms are increased levels of 3-methylglutaconic acid, neurologic deterioration and neutropenia. Other common features include progressive encephalopathy, movement abnormalities, delayed psychomotor development,impaired intellectual development, cataracts, seizures, and recurrent infections. The disease is caused by variants affecting the gene represented in this entry. 3-methylglutaconic aciduria 7A (MGCA7A) [MIM:619835] An autosomal dominant inborn error of metabolism with a highly variable phenotype. Primary disease symptoms are increased levels of 3-methylglutaconic acid, neurologic deterioration and neutropenia. Other common features include progressive encephalopathy, movement abnormalities, delayed psychomotor development, impaired intellectual development, cataracts, seizures, and recurrent infections. The disease is caused by variants affecting the gene represented in this entry. Neutropenia, severe congenital 9, autosomal dominant (SCN9) [MIM:619813] A form of severe congenital neutropenia, a disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. SCN9 is characterized by onset of neutropenia in the first years of life. Rare patients may exhibit additional features such as seizures, learning difficulties, or cataracts. Patients with SCN9 do not have 3-methylglutaconic aciduria. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Disaggregase activity is inhibited by ADP.

Domain organisation. The ankyrin-repeat region is necessary for ATP-dependent protein disaggregase activity. It plays an important role in stabilizing the substrate-bound homododecamer by mediating contacts between the two homohexamers.

Miscellaneous. Hexamers display robustness and can tolerate some mutant subunits without loss of activity. Subunits containing SCN9-linked variants Lys-496, Gly-561 and Cys-620 inhibit ATPase and disaggregase activities of the hexamer more severely than those containing MGCA7-linked variants Gly-408, Gly-475 and Val-591.

Similarity. Belongs to the ClpA/ClpB family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H078-1	1	yes
Q9H078-2	2
Q9H078-3	3
Q9H078-4	4
Q9H078-5	5

RefSeq proteins (4): NP_001245321, NP_001245322, NP_001245323, NP_110440 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001270	ClpA/B	Family
IPR002110	Ankyrin_rpt	Repeat
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR019489	Clp_ATPase_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR050130	ClpA_ClpB	Family

Pfam: PF07724, PF10431, PF12796

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (112 total): helix 29, sequence variant 27, strand 14, binding site 12, mutagenesis site 9, splice variant 4, repeat 4, turn 3, sequence conflict 3, chain 2, region of interest 2, transit peptide 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8FDS	X-RAY DIFFRACTION	1.65
8DEH	X-RAY DIFFRACTION	1.81
7XC5	X-RAY DIFFRACTION	2.1
7US2	ELECTRON MICROSCOPY	2.76
7TTS	ELECTRON MICROSCOPY	2.9
7TTR	ELECTRON MICROSCOPY	2.96
7XBK	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H078-F1	72.52	0.26

Functional residue map

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

Catalytic / active sites (1): 126–127 (cleavage; by parl)

Ligand- & substrate-binding residues (12): 348; 383; 384; 385; 386; 387; 388; 455; 496; 561; 620; 346

Post-translational modifications (1): 589

Mutagenesis-validated functional residues (9):

Position	Phenotype
178	shows higher order assembly but disaggregase activity is severely impaired by 70-80%.
257	shows higher order assembly but disaggregase activity is severely impaired by 70-80%.
387	loss of atp hydrolysis activity. loss of atp-dependent protein disaggregase activity.
417	no effect on atpase activity but shows decreased disaggregase activity.
430	decreased atp hydrolysis activity. loss of atp-dependent protein disaggregase activity.
431	decreased atp hydrolysis activity. loss of atp-dependent protein disaggregase activity.
455	loss of atp hydrolysis activity at ph 8.0. no effect on atp hydrolysis activity at ph 6.8. loss of atp-dependent protein
475	severely decreased atp hydrolysis activity. loss of atp-dependent protein disaggregase activity.
650	no effect on atp hydrolysis activity. loss of atp-dependent protein disaggregase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 438 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, MENSE_HYPOXIA_UP, AACYNNNNTTCCS_UNKNOWN, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GGAMTNNNNNTCCY_UNKNOWN, chr11q13, GGCNKCCATNK_UNKNOWN, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOCC_MITOCHONDRIAL_ENVELOPE, GNF2_CCNA1, GOBP_CELLULAR_RESPONSE_TO_HEAT

GO Biological Process (4): granulocyte differentiation (GO:0030851), cellular response to heat (GO:0034605), RIG-I signaling pathway (GO:0039529), antiviral innate immune response (GO:0140374)

GO Molecular Function (6): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ATP-dependent protein disaggregase activity (GO:0140545), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ATP-dependent activity	2
myeloid leukocyte differentiation	1
response to heat	1
cellular response to stress	1
cytoplasmic pattern recognition receptor signaling pathway	1
innate immune response	1
defense response to virus	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
protein-containing complex destabilizing activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrial envelope	1
organelle envelope lumen	1

Protein interactions and networks

STRING

4638 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLPB	CLPX	O76031	965
CLPB	GRPEL1	Q9HAV7	955
CLPB	CLPP	Q16740	927
CLPB	HSPD1	P10809	892
CLPB	HSPE1	P61604	873
CLPB	DNAJB1	P25685	872
CLPB	SP100	P23497	870
CLPB	TBX22	Q9Y458	868
CLPB	HSPA4	P34932	845
CLPB	YME1L1	Q96TA2	769
CLPB	TOR1A	O14656	719
CLPB	HSP90AB1	P08238	677
CLPB	HSP90AA1	P07900	676
CLPB	CACNA1S	Q13698	649
CLPB	STIP1	P31948	646

IntAct

183 interactions, top by confidence:

A	B	Type	Score
GSKIP	GSK3A	psi-mi:“MI:0914”(association)	0.800
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
PRELID1	TRIAP1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UCHL3	CLPB	psi-mi:“MI:0915”(physical association)	0.640
SEC16A	SEC13	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NAP1L5	IQGAP1	psi-mi:“MI:0914”(association)	0.640
IRS4	PIK3R2	psi-mi:“MI:0914”(association)	0.640
CLPB	CEP70	psi-mi:“MI:0915”(physical association)	0.560
CEP70	CLPB	psi-mi:“MI:0915”(physical association)	0.560
CLPB	TTF2	psi-mi:“MI:0915”(physical association)	0.550
DHRS4	NDUFS2	psi-mi:“MI:0914”(association)	0.530
CHEK1	HAX1	psi-mi:“MI:0914”(association)	0.530
PINK1	CLUH	psi-mi:“MI:0914”(association)	0.530
UCHL3	ZMYM6	psi-mi:“MI:0914”(association)	0.530
HAX1	CHEK1	psi-mi:“MI:0914”(association)	0.530
TIMP3	ZZEF1	psi-mi:“MI:0914”(association)	0.530
ANGPTL7	TCP1	psi-mi:“MI:0914”(association)	0.530
CLPB	CLUH	psi-mi:“MI:0914”(association)	0.530
ECEL1	CLGN	psi-mi:“MI:0914”(association)	0.530
PSMB8	PSMA2	psi-mi:“MI:0914”(association)	0.530
TUSC2	HSPA8	psi-mi:“MI:0914”(association)	0.530
WNT4	TOMM40	psi-mi:“MI:0914”(association)	0.530
MDFI	CLPB	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (274): CLPB (Two-hybrid), CLPB (Affinity Capture-MS), ERCC6L (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), MGEA5 (Affinity Capture-MS), TTF2 (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS), CLPB (Affinity Capture-MS)

ESM2 similar proteins: A0A1L7TZE5, A0A559KX76, A1C7E4, A1CS00, A1DHW6, A2QCU8, A6SDQ3, A7F045, B0XTS1, B2WKR4, B6Q4Z5, B8M7Q5, B8NGT5, O22781, O43463, O54864, P0CY36, P93025, P97443, Q00659, Q0CY32, Q0E908, Q0VD24, Q28CQ7, Q2NL30, Q2UES9, Q2UFN8, Q32PH7, Q4IJ84, Q4R3E0, Q4WVM1, Q4X0A9, Q5BHD6, Q5E9N5, Q5F3W5, Q5I0M0, Q5PP37, Q5RB81, Q60649, Q6DGD3

Diamond homologs: A0M8T3, A1X154, A4D7T3, C9JTQ0, Q00PJ3, Q05823, Q05921, Q07DV3, Q07DX6, Q07DY6, Q07DZ7, Q07E17, Q07E30, Q07E43, Q09YH1, Q09YI3, Q09YJ5, Q09YK6, Q09YN0, Q108U1, Q2IBB1, Q2IBB4, Q2IBE3, Q2IBF5, Q2IBG0, Q2QL84, Q2QLA4, Q2QLB5, Q2QLC6, Q2QLG0, Q2QLH1, Q5E9N5, Q8IWZ3, Q8VD46, Q8WMX6, Q8WMX7, Q8WMX8, Q8WWH4, Q9FY48, Q9H078

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 215 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
Mitochondrial protein degradation	12	9.8×	2e-06
Respiratory electron transport	12	8.2×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	6	11.3×	4e-03
aerobic respiration	7	9.1×	4e-03
mitochondrion organization	8	6.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	15
Uncertain significance	438
Likely benign	300
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074465	NM_001258392.3(CLPB):c.1293dup (p.Asp432fs)	Pathogenic
1427364	NC_000011.9:g.(?72145096)(72145518_?)del	Pathogenic
1452426	NM_001258392.3(CLPB):c.532C>T (p.Arg178Ter)	Pathogenic
1676583	NM_001258392.3(CLPB):c.1073C>A (p.Thr358Lys)	Pathogenic
1676584	NM_001258392.3(CLPB):c.1591C>G (p.Arg531Gly)	Pathogenic
1676587	NM_001258392.3(CLPB):c.1190C>T (p.Pro397Leu)	Pathogenic
1676588	NM_001258392.3(CLPB):c.1588G>A (p.Gly530Arg)	Pathogenic
1684623	NM_001258392.3(CLPB):c.1167+5G>A	Pathogenic
1700633	NM_001258392.3(CLPB):c.1813_1814delinsAA (p.Ala605Lys)	Pathogenic
187780	NM_001258392.3(CLPB):c.1215_1217inv (p.Glu405_Gly406delinsAspPro)	Pathogenic
187781	NM_001258392.3(CLPB):c.1847G>T (p.Gly616Val)	Pathogenic
187782	NM_001258392.3(CLPB):c.1682C>T (p.Ala561Val)	Pathogenic
187784	NM_001258392.3(CLPB):c.1760A>G (p.Tyr587Cys)	Pathogenic
187786	NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter)	Pathogenic
187788	NM_001258392.3(CLPB):c.871A>T (p.Lys291Ter)	Pathogenic
192392	NM_001258392.3(CLPB):c.1595del (p.Ile532fs)	Pathogenic
2042071	NM_001258392.3(CLPB):c.278dup (p.Pro94fs)	Pathogenic
2136144	NM_001258392.3(CLPB):c.790C>T (p.Gln264Ter)	Pathogenic
2151624	NM_001258392.3(CLPB):c.1017C>G (p.Tyr339Ter)	Pathogenic
2296567	NM_001258392.3(CLPB):c.1165G>T (p.Glu389Ter)	Pathogenic
2426947	NC_000011.9:g.(?72004411)(72006712_?)del	Pathogenic
2426950	NC_000011.9:g.(?72145398)(72145517_?)del	Pathogenic
2426951	NC_000011.9:g.(?72145398)(72150823_?)del	Pathogenic
2504553	NM_001258392.3(CLPB):c.1014G>A (p.Trp338Ter)	Pathogenic
2506998	NM_001258392.3(CLPB):c.449_455del (p.Val150fs)	Pathogenic
279604	NM_001258392.3(CLPB):c.658C>T (p.Arg220Ter)	Pathogenic
2809209	NM_001258392.3(CLPB):c.1341_1344del (p.Asp448fs)	Pathogenic
3638533	NM_001258392.3(CLPB):c.787del (p.Leu263fs)	Pathogenic
4721970	NM_001258392.3(CLPB):c.319del (p.Val107fs)	Pathogenic
4731503	NM_001258392.3(CLPB):c.788del (p.Leu263fs)	Pathogenic

SpliceAI

2750 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72293612:CTAC:C	acceptor_gain	1.0000
11:72293614:AC:A	acceptor_gain	1.0000
11:72293615:CC:C	acceptor_gain	1.0000
11:72293615:CCTG:C	acceptor_loss	1.0000
11:72293620:CGG:C	acceptor_gain	1.0000
11:72293621:G:T	acceptor_gain	1.0000
11:72294017:CTCA:C	donor_loss	1.0000
11:72294018:TCA:T	donor_loss	1.0000
11:72294019:CACCT:C	donor_loss	1.0000
11:72294020:A:AG	donor_loss	1.0000
11:72294021:C:G	donor_loss	1.0000
11:72294021:CCT:C	donor_gain	1.0000
11:72294124:GGCC:G	acceptor_loss	1.0000
11:72294125:GCC:G	acceptor_loss	1.0000
11:72294126:CCTG:C	acceptor_loss	1.0000
11:72294316:C:A	donor_gain	1.0000
11:72294323:A:AC	donor_gain	1.0000
11:72294323:ACT:A	donor_gain	1.0000
11:72294323:ACTCT:A	donor_gain	1.0000
11:72294324:C:CA	donor_gain	1.0000
11:72294324:CT:C	donor_gain	1.0000
11:72294324:CTC:C	donor_gain	1.0000
11:72294324:CTCT:C	donor_gain	1.0000
11:72294324:CTCTC:C	donor_gain	1.0000
11:72294327:T:A	donor_gain	1.0000
11:72294344:AGTT:A	donor_gain	1.0000
11:72294347:T:A	donor_gain	1.0000
11:72294454:CAGGT:C	acceptor_gain	1.0000
11:72294614:TCTTA:T	donor_loss	1.0000
11:72294616:TTA:T	donor_loss	1.0000

AlphaMissense

4414 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72294044:C:T	G618D	1.000
11:72294344:A:G	L584P	1.000
11:72294391:G:C	F568L	1.000
11:72294391:G:T	F568L	1.000
11:72294393:A:G	F568L	1.000
11:72294413:C:G	R561P	1.000
11:72294414:G:C	R561G	1.000
11:72294416:C:T	G560E	1.000
11:72294417:C:G	G560R	1.000
11:72294417:C:T	G560R	1.000
11:72294421:A:C	F558L	1.000
11:72294421:A:T	F558L	1.000
11:72294422:A:C	F558C	1.000
11:72294422:A:G	F558S	1.000
11:72294423:A:G	F558L	1.000
11:72294424:C:A	E557D	1.000
11:72294424:C:G	E557D	1.000
11:72294426:C:T	E557K	1.000
11:72294624:A:G	L549P	1.000
11:72295580:A:C	N496K	1.000
11:72295580:A:T	N496K	1.000
11:72295590:A:C	M493R	1.000
11:72295590:A:T	M493K	1.000
11:72295641:A:G	L476P	1.000
11:72295644:C:G	R475P	1.000
11:72295647:C:T	G474D	1.000
11:72295648:C:G	G474R	1.000
11:72301807:T:A	D472V	1.000
11:72301808:C:G	D472H	1.000
11:72301813:A:G	L470P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000447 (11:72384860 T>C), RS1000016761 (11:72387313 C>T), RS1000018010 (11:72393261 A>C), RS1000058522 (11:72420209 C>T), RS1000069155 (11:72387672 G>C), RS1000069484 (11:72292961 G>A), RS1000095071 (11:72331723 G>A), RS1000114225 (11:72432133 A>T), RS1000119431 (11:72371525 T>A), RS1000147898 (11:72291468 T>C), RS1000148309 (11:72338115 G>C), RS1000167789 (11:72364670 CA>C), RS1000179492 (11:72341398 T>C), RS1000192663 (11:72382086 C>T), RS1000197719 (11:72367554 C>A,T)

Disease associations

OMIM: gene MIM:616254 | disease phenotypes: MIM:616271, MIM:619835, MIM:619813, MIM:250950, MIM:613107

GenCC curated gene-disease

Disease	Classification	Inheritance
3-methylglutaconic aciduria, type VIIB	Definitive	Autosomal recessive
neutropenia, severe congenital, 9, autosomal dominant	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (8): 3-methylglutaconic aciduria, type VIIB (MONDO:0014561), 3-methylglutaconic aciduria, type VIIA (MONDO:0859237), neutropenia, severe congenital, 9, autosomal dominant (MONDO:0030726), microcytic anemia (MONDO:0001245), 3-methylglutaconic aciduria (MONDO:0017359), premature menopause (MONDO:0001119), neutropenia (MONDO:0001475), neutropenia, severe congenital, 2, autosomal dominant (MONDO:0013139)

Orphanet (3): 3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome (Orphanet:445038), 3-methylglutaconic aciduria (Orphanet:289902), Autosomal dominant severe congenital neutropenia (Orphanet:486)

HPO phenotypes

121 total (30 of 121 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000107	Renal cyst
HP:0000121	Nephrocalcinosis
HP:0000155	Oral ulcer
HP:0000211	Trismus
HP:0000230	Gingivitis
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000414	Bulbous nose
HP:0000518	Cataract
HP:0000629	Periorbital fullness
HP:0000639	Nystagmus
HP:0000704	Periodontitis
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0000938	Osteopenia
HP:0001028	Hemangioma
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001298	Encephalopathy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005846_11	Heart rate response to recovery post exercise (10 sec)	2.000000e-11
GCST006627_93	Diastolic blood pressure	3.000000e-16
GCST008839_174	Height	1.000000e-08
GCST010796_1778	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST90002401_183	Platelet distribution width	3.000000e-16

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009185	heart rate response to recovery post exercise
EFO:0006336	diastolic blood pressure
EFO:0004327	electrocardiography
EFO:0007984	platelet component distribution width

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009503	Neutropenia	C15.378.243.750.184.564; C15.378.553.546.184.564
C579867	3-Methylglutaconic Aciduria (supp.)
C567748	Neutropenia, Severe Congenital, Autosomal Dominant 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression, decreases expression	3
sodium arsenite	decreases expression, increases expression	2
bisphenol S	affects expression, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
sodium arsenate	decreases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
entinostat	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benzo(a)pyrene	increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression, increases expression	1
Ivermectin	decreases expression	1
Oxygen	decreases expression	1
Ozone	increases abundance, affects cotreatment, increases oxidation	1
Theophylline	affects cotreatment, decreases expression, increases expression	1
Thiram	increases expression	1
Valproic Acid	increases expression	1
Vitallium	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9C4	Ubigene HEK293 CLPB KO	Transformed cell line	Female
CVCL_E1TV	HAP1 CLPB (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00125723	PHASE4	COMPLETED	FIRST - Study of Pegfilgrastim Administered in the First and Subsequent Cycles of Myelosuppressive Chemotherapy
NCT00194857	PHASE4	TERMINATED	Treatment of Anemia and Neutropenia in HIV/HCV Coinfected Patients Treated With Pegylated Interferon and Ribavirin
NCT00257790	PHASE4	COMPLETED	The Tobramycin Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00686543	PHASE4	COMPLETED	Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01114165	PHASE4	COMPLETED	Value of the LightCycler® SeptiFast Test MGRADE for the Pathogen Detection in Neutropenic Hematological Patients
NCT01135589	PHASE4	UNKNOWN	Micafungin Prevention Study for Fungal Disease in Child Receiving Allogenic Hematopoietic Stem Cell Transplantation
NCT01571518	PHASE4	UNKNOWN	Prevention of Neutropenia After Using G-CSF With TAC Chemotherapy
NCT02621905	PHASE4	COMPLETED	Steady-State Comparative Bioavailability Study in Prophylaxis Patients of Lozanoc® 50 mg With Sporanox® 100 mg
NCT02967341	PHASE4	UNKNOWN	Blood Draw Validation for Ciprofloxacin Pharmacokinetic Research in Pediatric Cancer Patients
NCT04009941	PHASE4	COMPLETED	Efficacy and Safety of 4.5mg PEG-rhG-CSF Per Cycle in Preventing Neutropenia After Intensive Chemotherapy for Breast Cancer
NCT04904614	PHASE4	COMPLETED	Letermovir Use in Heart Transplant Recipients
NCT05626530	PHASE4	RECRUITING	Letermovir for Secondary Prophylaxis in Solid Organ Transplant Recipients
NCT06145321	PHASE4	ACTIVE_NOT_RECRUITING	Continuous Versus Bolus Administration of G-CSF in Children With Cancer
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001338	PHASE3	COMPLETED	A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00002658	PHASE3	UNKNOWN	Combination Chemotherapy, Biological Therapy, and Bone Marrow Transplantation in Treating Patients With Acute Myeloid Leukemia
NCT00002719	PHASE3	COMPLETED	Combination Chemotherapy With or Without G-CSF in Treating Older Patients With Acute Myeloid Leukemia
NCT00003739	PHASE3	COMPLETED	Antibiotic Therapy With or Without G-CSF in Treating Children With Neutropenia and Fever Caused by Chemotherapy
NCT00020865	PHASE3	UNKNOWN	Levofloxacin Compared With Cefepime in Treating Cancer Patients With Fever and Neutropenia
NCT00035594	PHASE3	COMPLETED	Pegfilgrastim as Support to Advanced Breast Cancer Patients Receiving Chemotherapy
NCT00044486	PHASE3	COMPLETED	Prophylaxis Trial of Posaconazole Versus Standard Azole Therapy for Neutropenic Patients (Study P01899)
NCT00107081	PHASE3	TERMINATED	Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting
NCT00445497	PHASE3	UNKNOWN	Early Hospital Discharge or Standard Inpatient Care in Cancer Patients Receiving Antibiotics for Febrile Neutropenia
NCT00529282	PHASE3	TERMINATED	A Study of Ceftobiprole in Patients With Fever and Neutropenia.
NCT00627393	PHASE3	COMPLETED	Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
NCT00770172	PHASE3	COMPLETED	G-CSF in Preventing Neutropenia in Patients With Solid Tumors Who Are Receiving Chemotherapy
NCT00784368	PHASE3	COMPLETED	A Pharmacokinetic Study of JK1211(Itraconazole [Itrizole]) Oral Solution in Participants With Deep Mycosis and Those With Febrile Neutropenia Suspected of Fungal Infection
NCT00806351	PHASE3	TERMINATED	An Evaluation Of The Effectiveness And Safety Of Anidulafungin Compared To Caspofungin For The Treatment Of Serious Fungal Infection Due To Candida In Patients With A Dysfunctional Immune System
NCT00911170	PHASE3	COMPLETED	PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study
NCT01307579	PHASE3	COMPLETED	Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia