CLPP

Summary

CLPP (caseinolytic mitochondrial matrix peptidase proteolytic subunit, HGNC:2084) is a protein-coding gene on chromosome 19p13.3, encoding ATP-dependent Clp protease proteolytic subunit, mitochondrial (Q16740). Protease component of the ClpXP complex that cleaves peptides and various proteins in an ATP-dependent process.

The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane.

Source: NCBI Gene 8192 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Perrault syndrome 3 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 238 total — 12 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_006012

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2084
Approved symbol	CLPP
Name	caseinolytic mitochondrial matrix peptidase proteolytic subunit
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125656
Ensembl biotype	protein_coding
OMIM	601119
Entrez	8192

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 retained_intron

ENST00000245816, ENST00000594780, ENST00000596070, ENST00000596149, ENST00000596605, ENST00000597326, ENST00000646643, ENST00000715787, ENST00000926271, ENST00000926272

RefSeq mRNA: 1 — MANE Select: NM_006012 NM_006012

CCDS: CCDS12162

Canonical transcript exons

ENST00000245816 — 6 exons

Exon	Start	End
ENSE00002987749	6368538	6370242
ENSE00003484252	6366258	6366363
ENSE00003540033	6362446	6362542
ENSE00003667614	6361869	6361940
ENSE00003689024	6364452	6364639
ENSE00004027934	6361531	6361772

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.2497 / max 273.6877, expressed in 1823 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173462	37.6618	1812
173463	11.9723	1739
173461	4.4571	1643
173468	2.1750	1128
173466	1.7752	1135
173470	0.9027	523
173465	0.6495	429
173469	0.6249	341
173464	0.5888	294
173467	0.4424	226

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	97.45	gold quality
gastrocnemius	UBERON:0001388	97.15	gold quality
mucosa of transverse colon	UBERON:0004991	97.04	gold quality
apex of heart	UBERON:0002098	96.92	gold quality
muscle of leg	UBERON:0001383	96.76	gold quality
right adrenal gland	UBERON:0001233	96.68	gold quality
left adrenal gland	UBERON:0001234	96.47	gold quality
right lobe of liver	UBERON:0001114	96.42	gold quality
right adrenal gland cortex	UBERON:0035827	96.42	gold quality
left adrenal gland cortex	UBERON:0035825	96.31	gold quality
body of stomach	UBERON:0001161	96.19	gold quality
lower esophagus mucosa	UBERON:0035834	95.99	gold quality
stromal cell of endometrium	CL:0002255	95.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.93	gold quality
mucosa of stomach	UBERON:0001199	95.92	gold quality
lower esophagus	UBERON:0013473	95.79	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.79	gold quality
adenohypophysis	UBERON:0002196	95.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.62	gold quality
left coronary artery	UBERON:0001626	95.57	gold quality
right atrium auricular region	UBERON:0006631	95.57	gold quality
heart left ventricle	UBERON:0002084	95.55	gold quality
left uterine tube	UBERON:0001303	95.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.38	gold quality
adrenal cortex	UBERON:0001235	95.33	gold quality
ganglionic eminence	UBERON:0004023	95.29	gold quality
cardiac ventricle	UBERON:0002082	95.28	gold quality
esophagus	UBERON:0001043	95.19	gold quality
cortical plate	UBERON:0005343	95.19	gold quality
metanephros cortex	UBERON:0010533	95.18	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.27
E-MTAB-7052	no	78.42
E-HCAD-13	no	2.85
E-CURD-112	no	2.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RELB

miRNA regulators (miRDB)

11 targeting CLPP, 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-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6787-3P	97.75	66.17	1233

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 24)

• the N-terminal peptide of ClpP is a structural component of the substrate translocation channel and may play an important functional role as well (PMID:15522782)
• hClpX can regulate the appearance of hClpP peptidase activity in mitochondria and might affect the nature of the degradation products released during ATP-dependent proteolytic cycles (PMID:16115876)
• We propose that decreased levels of mitochondrial proteases Lon and ClpP may allow heat shock protein 60 substrate proteins to go through more folding attempts (PMID:18378094)
• Deletion of PaClpP, leads to an unexpected healthy phenotype and increased lifespan of the fungal ageing model organism Podospora anserina and This phenotype can be reverted by expression of human ClpP. (PMID:23360988)
• Perrault syndrome is caused by recessive mutations in CLPP. (PMID:23541340)
• Optical trapping to assay single-molecule ClpXP unfolding and translocation of substrates consisting of domains with varying stabilities and sequences; find that ClpXP unfolds most domains by a single pathway, with kinetics that depend on the native fold and structural stability. (PMID:25083874)
• ClpP proteases from E. coli, S. aureus, and human mitochondria exhibit preferences for certain amino acids in the P1, P2, and P3 positions . (PMID:26606371)
• Mitochondrial overexpression of human ClpP protects HeLa cells from killing by cisplatin. Overexpression of human ClpP desensitizes cells to cisplatin. (PMID:26675528)
• ere we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2 (PMID:26970254)
• Data indicate endopeptidase Clp (ClpP) mutation identified in two patients with Perrault syndrome type 3 in a Turkish family. (PMID:27087618)
• we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. (PMID:27154400)
• Data suggest that tumors exploit ClpXP-directed proteostasis to maintain mitochondrial bioenergetics, buffer oxidative stress, and enable metastatic competence. (PMID:27389535)
• Autophagy compensates impaired energy metabolism in CLPXP-deficient Podospora anserina strains and extends healthspan. (PMID:28449241)
• ClpP is selectively decreased in alphaSyn-expressing cell culture and neurons derived from iPS cells of PD patient carrying alphaSyn A53T mutant, and in dopaminergic neurons of alphaSyn A53T mice and PD patient postmortem brains. ClpP loss damages mitochondria. Overexpression causes oxidative stress and suppresses alphaSyn phosphorylation. alphaSyn WT and A53T mutant interact with ClpP and suppress its peptidase activity. (PMID:30877431)
• Results found that CLPP influenced mitochondrial respiration only under conditions of oxidative stress. (PMID:30878663)
• Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease. (PMID:32342250)
• Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM). (PMID:32399598)
• Mitochondrial Caseinolytic Protease P: A Possible Novel Prognostic Marker and Therapeutic Target in Cancer. (PMID:34207660)
• Substrate Profiling of Mitochondrial Caseinolytic Protease P via a Site-Specific Photocrosslinking Approach. (PMID:34847623)
• Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA. (PMID:34943861)
• CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis. (PMID:35240691)
• Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma. (PMID:35905743)
• Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma. (PMID:37923710)
• HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells. (PMID:38419499)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clpp	ENSDARG00000020679
mus_musculus	Clpp	ENSMUSG00000002660
rattus_norvegicus	Clpp	ENSRNOG00000047052
drosophila_melanogaster	ClpP	FBGN0032229
caenorhabditis_elegans		WBGENE00014172

Protein

Protein identifiers

ATP-dependent Clp protease proteolytic subunit, mitochondrial — Q16740 (reviewed: Q16740)

Alternative names: Caseinolytic mitochondrial matrix peptidase proteolytic subunit, Endopeptidase Clp

All UniProt accessions (5): A0A2R8YEF5, Q16740, M0QXE9, M0QYV5, M0R208

UniProt curated annotations — full annotation on UniProt →

Function. Protease component of the ClpXP complex that cleaves peptides and various proteins in an ATP-dependent process. Has low peptidase activity in the absence of CLPX. The ClpXP complex can degrade CSN1S1, CSN2 and CSN3, as well as synthetic peptides (in vitro) and may be responsible for a fairly general and central housekeeping function rather than for the degradation of specific substrates. Cleaves PINK1 in the mitochondrion.

Subunit / interactions. Fourteen CLPP subunits assemble into 2 heptameric rings which stack back to back to give a disk-like structure with a central cavity. Component of the ClpXP complex formed by the assembly of two CLPP heptameric rings with two CLPX hexameric rings, giving rise to a symmetrical structure with two central CLPP rings flanked by a CLPX ring at either end of the complex.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Detected in liver (at protein level). Predominantly expressed in skeletal muscle. Intermediate levels in heart, liver and pancreas. Low in brain, placenta, lung and kidney.

Disease relevance. Perrault syndrome 3 (PRLTS3) [MIM:614129] An autosomal recessive, sex-influenced disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile. A spectrum of additional clinical features, including cerebellar ataxia, learning disability, and peripheral neuropathy, have been described in some PRLTS3 affected individuals. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S14 family.

RefSeq proteins (1): NP_006003* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001907	ClpP	Family
IPR018215	ClpP_Ser_AS	Active_site
IPR023562	ClpP/TepA	Family
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily
IPR033135	ClpP_His_AS	Active_site

Pfam: PF00574

Enzyme classification (BRENDA):

• EC 3.4.21.92 — Endopeptidase Clp (BRENDA: 73 organisms, 159 substrates, 60 inhibitors, 27 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-SUCCINYL-LEU-TYR-7-AMIDO-4-METHYLCOUMARIN	0.52–1.1	5
ARC-SSRA	0.0005–0.14	4
LAMBDA O CM-TITIIN	0.011–0.041	4
INSULIN CHAIN B	0.04–0.3167	3
CM-TITIN-SSRA	0.0024–0.08	2
FEGFP-SSRA	—	2
LAMBDA O ARC	0.0044–0.013	2
SUC-LLVY-4-METHYLCOUMARIN-7-AMIDE	0.065	2
31-KNOTTED METHYLTRANSFERASE YBEA-SSRA	0.0013	1
ATP	0.21	1
N-SUCCINYL-LEU-TYR 4-METHYLCOUMARIN 7-AMIDE	1.3	1
GLUCAGON	—	0
OXIDIZED INSULIN B-CHAIN	—	0
PHE-ALA-PRO-HIS-MET-ALA-LEU-VAL-PRO-VAL	—	0
SUCCINYL-LLVY-7-AMIDO-4-METHYLCOUMARIN	—	0

UniProt features (32 total): strand 11, helix 7, sequence variant 3, mutagenesis site 2, active site 2, modified residue 2, transit peptide 1, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
8HGK	X-RAY DIFFRACTION	1.9
8I7X	X-RAY DIFFRACTION	1.99
6DL7	X-RAY DIFFRACTION	2
1TG6	X-RAY DIFFRACTION	2.1
7WH5	X-RAY DIFFRACTION	2.13
8YLB	X-RAY DIFFRACTION	2.15
7UVM	X-RAY DIFFRACTION	2.19
9DW3	ELECTRON MICROSCOPY	2.4
9KUF	ELECTRON MICROSCOPY	2.45
9DKW	ELECTRON MICROSCOPY	2.49
7VP9	X-RAY DIFFRACTION	2.55
8YPA	X-RAY DIFFRACTION	2.67
9DQK	X-RAY DIFFRACTION	2.75
6BBA	X-RAY DIFFRACTION	2.8
7UW0	X-RAY DIFFRACTION	2.8
8W7E	X-RAY DIFFRACTION	2.8
9DW0	ELECTRON MICROSCOPY	2.8
9DKV	ELECTRON MICROSCOPY	2.81
7UVR	X-RAY DIFFRACTION	2.86
8WUZ	X-RAY DIFFRACTION	2.9
8W7C	X-RAY DIFFRACTION	3
6H23	X-RAY DIFFRACTION	3.09
7UVN	X-RAY DIFFRACTION	3.11
9DQL	X-RAY DIFFRACTION	3.2
7UVU	X-RAY DIFFRACTION	3.24
9DW1	ELECTRON MICROSCOPY	3.4
9YKZ	ELECTRON MICROSCOPY	3.5
9WAS	X-RAY DIFFRACTION	3.52
9PB1	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16740-F1	82.68	0.62

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 (2): 153 (nucleophile); 178

Post-translational modifications (2): 200, 211

Mutagenesis-validated functional residues (2):

Position	Phenotype
58–61	abolishes protease activity.
153	abolishes protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 165 (showing top): MORF_DNMT1, MORF_ESPL1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MORF_BUB3, BOGNI_TREATMENT_RELATED_MYELOID_LEUKEMIA_UP, DOUGLAS_BMI1_TARGETS_UP, WONG_MITOCHONDRIA_GENE_MODULE, GOBP_MEMBRANE_PROTEIN_PROTEOLYSIS, GOBP_PROTEIN_CATABOLIC_PROCESS, RAMPON_ENRICHED_LEARNING_ENVIRONMENT_LATE_UP, GOCC_MITOCHONDRIAL_MATRIX, GOBP_PROTEOLYSIS, SMITH_TERT_TARGETS_UP

GO Biological Process (5): proteolysis (GO:0006508), protein quality control for misfolded or incompletely synthesized proteins (GO:0006515), membrane protein proteolysis (GO:0033619), mitochondrial protein catabolic process (GO:0035694), obsolete proteolysis involved in protein catabolic process (GO:0051603)

GO Molecular Function (9): endopeptidase activity (GO:0004175), ATP-dependent peptidase activity (GO:0004176), serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), identical protein binding (GO:0042802), ATPase binding (GO:0051117), protein binding (GO:0005515), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), endopeptidase Clp complex (GO:0009368)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	3
protein catabolic process	2
mitochondrion	2
protein metabolic process	1
proteolysis	1
mitochondrion organization	1
ATP-dependent activity	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
protein binding	1
enzyme binding	1
binding	1
serine hydrolase activity	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
catalytic complex	1

Protein interactions and networks

STRING

4174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLPP	CLPX	O76031	998
CLPP	TBX22	Q9Y458	994
CLPP	CLPB	Q9H078	927
CLPP	RPS16	P17008	885
CLPP	YME1L1	Q96TA2	854
CLPP	LONP1	P36776	845
CLPP	HSPE1	P61604	816
CLPP	HSPD1	P10809	813
CLPP	GRPEL1	Q9HAV7	810
CLPP	SPX	Q9BT56	723
CLPP	ERAL1	O75616	718
CLPP	AFG3L2	Q9Y4W6	716
CLPP	RPS2	P15880	715
CLPP	HSPA9	P30036	710
CLPP	SPG7	Q9UQ90	707

IntAct

143 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.670
MRPS30	GTPBP10	psi-mi:“MI:0914”(association)	0.640
TNPO3	CLPP	psi-mi:“MI:0915”(physical association)	0.560
GRN	CLPP	psi-mi:“MI:0915”(physical association)	0.560
CLPP	PLSCR4	psi-mi:“MI:0915”(physical association)	0.560
CLPP	DTX2	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2	CLPP	psi-mi:“MI:0915”(physical association)	0.560
EFEMP1	CLPP	psi-mi:“MI:0915”(physical association)	0.560
CLPP	ABI2	psi-mi:“MI:0915”(physical association)	0.560
CLPP	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
PPP2CA	CLPP	psi-mi:“MI:0915”(physical association)	0.560
CLPP	P4HA3	psi-mi:“MI:0915”(physical association)	0.560
CLPP	TNPO3	psi-mi:“MI:0915”(physical association)	0.560
PSMB1	CLPP	psi-mi:“MI:0915”(physical association)	0.560
NUTF2	CLPP	psi-mi:“MI:0915”(physical association)	0.560
	CLPP	psi-mi:“MI:0915”(physical association)	0.560
CLPP	C14orf119	psi-mi:“MI:0915”(physical association)	0.560
DNM2	CLPP	psi-mi:“MI:0915”(physical association)	0.560
WFS1	CLPP	psi-mi:“MI:0915”(physical association)	0.560
GDAP1	CLPP	psi-mi:“MI:0915”(physical association)	0.560
JPH3	CLPP	psi-mi:“MI:0915”(physical association)	0.560
APP	CLPP	psi-mi:“MI:0915”(physical association)	0.560
SNCA	CLPP	psi-mi:“MI:0915”(physical association)	0.560
HTT	CLPP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (840): CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS), CLPP (Affinity Capture-MS)

ESM2 similar proteins: A1BI15, A2YQ56, A4SDA4, A8WPG6, B9KHZ4, C4K4P2, O34125, O88696, P32232, P36776, P93648, P93655, Q07NN6, Q135W7, Q16740, Q1GPH5, Q1RJH2, Q27539, Q2G3T3, Q2IWZ4, Q2KHU4, Q2RU45, Q2S2L8, Q3ATL3, Q3B5V8, Q4FQB9, Q59993, Q59HJ6, Q5N1P6, Q5PBD0, Q5Z062, Q69UZ3, Q7V992, Q82CA6, Q8CGK3, Q8DLI2, Q8KC73, Q8L770, Q8TB37, Q8YQX8

Diamond homologs: A1K783, A1S4X5, A1USA7, A1VE85, A1WUM7, A3PKS1, A4WSH8, A4XTZ5, A5CXJ8, A5EKA8, A5W635, A6SY74, A7ILC6, A8EYM5, A8GSH5, A8HYF2, A8WPG6, A9ISA4, A9M5C2, A9W5F5, B0CGR1, B0SZQ2, B1J692, B1LW28, B1Z9C7, B2S5W1, B3Q7P5, B4EU53, B6JGU7, B7KNT0, B8DNL4, B8GX16, B8IN26, B9KHZ4, B9KJU9, C0R2W3, C0RJ81, C4K1D4, C5BTJ0, O30612

SIGNOR signaling

0 interactions.

Enriched among interaction partners

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

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex I biogenesis	6	12.1×	2e-03
Mitochondrial protein degradation	8	11.1×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	9
Uncertain significance	71
Likely benign	99
Benign	32

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1356365	NM_006012.4(CLPP):c.12_33dup (p.Val12fs)	Pathogenic
1411562	NM_006012.4(CLPP):c.491del (p.Pro164fs)	Pathogenic
2031987	NM_006012.4(CLPP):c.585_586insAT (p.Glu196fs)	Pathogenic
2138190	NM_006012.4(CLPP):c.21del (p.Ala10fs)	Pathogenic
2579749	NM_006012.4(CLPP):c.383_399dup (p.Asp134fs)	Pathogenic
3601032	NM_006012.4(CLPP):c.328del (p.Ser110fs)	Pathogenic
3601044	NM_006012.4(CLPP):c.661G>T (p.Glu221Ter)	Pathogenic
545503	NM_006012.4(CLPP):c.624C>G (p.Ile208Met)	Pathogenic
55868	NM_006012.4(CLPP):c.433A>C (p.Thr145Pro)	Pathogenic
55869	NM_006012.4(CLPP):c.440G>C (p.Cys147Ser)	Pathogenic
55870	NM_006012.4(CLPP):c.270+4A>G	Pathogenic
593703	NM_006012.4(CLPP):c.367+2T>C	Pathogenic
1332812	NM_006012.4(CLPP):c.299T>C (p.Ile100Thr)	Likely pathogenic
2138191	NM_006012.4(CLPP):c.661G>A (p.Glu221Lys)	Likely pathogenic
2171411	NM_006012.4(CLPP):c.199-1G>C	Likely pathogenic
2584518	NM_006012.4(CLPP):c.484G>A (p.Gly162Ser)	Likely pathogenic
3068435	NM_006012.2(CLPP):c.-995_270+222del	Likely pathogenic
3358989	NM_006012.4(CLPP):c.262A>T (p.Met88Leu)	Likely pathogenic
3601043	NM_006012.4(CLPP):c.400G>C (p.Asp134His)	Likely pathogenic
813818	NM_006012.4(CLPP):c.233G>C (p.Arg78Pro)	Likely pathogenic
869195	NM_006012.4(CLPP):c.439T>A (p.Cys147Ser)	Likely pathogenic

SpliceAI

511 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6361574:G:T	donor_gain	1.0000
19:6361769:GACG:G	donor_gain	1.0000
19:6361770:ACGGT:A	donor_loss	1.0000
19:6361773:G:GG	donor_gain	1.0000
19:6361773:GTACG:G	donor_loss	1.0000
19:6361774:T:G	donor_loss	1.0000
19:6361863:CCCCA:C	acceptor_loss	1.0000
19:6361864:CCCAG:C	acceptor_loss	1.0000
19:6361865:CCAG:C	acceptor_loss	1.0000
19:6361866:CAGG:C	acceptor_loss	1.0000
19:6361867:A:AG	acceptor_gain	1.0000
19:6361867:A:AT	acceptor_loss	1.0000
19:6361867:AG:A	acceptor_gain	1.0000
19:6361868:G:GA	acceptor_loss	1.0000
19:6361868:G:GG	acceptor_gain	1.0000
19:6361868:GG:G	acceptor_gain	1.0000
19:6361868:GGGTC:G	acceptor_gain	1.0000
19:6361936:GCCCG:G	donor_gain	1.0000
19:6362542:GGT:G	donor_loss	1.0000
19:6362543:G:GC	donor_loss	1.0000
19:6362543:G:GG	donor_gain	1.0000
19:6362544:T:A	donor_loss	1.0000
19:6364449:CA:C	acceptor_loss	1.0000
19:6364450:A:AC	acceptor_loss	1.0000
19:6364450:A:AG	acceptor_gain	1.0000
19:6364450:AG:A	acceptor_gain	1.0000
19:6364450:AGGT:A	acceptor_gain	1.0000
19:6364450:AGGTG:A	acceptor_gain	1.0000
19:6364451:G:GA	acceptor_gain	1.0000
19:6364451:GG:G	acceptor_gain	1.0000

AlphaMissense

1794 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6361906:T:C	L79P	1.000
19:6361926:T:C	C86R	1.000
19:6362483:T:C	L103P	1.000
19:6362492:T:C	L106P	1.000
19:6364470:G:A	G129D	1.000
19:6364485:A:T	D134V	1.000
19:6364525:C:G	C147W	1.000
19:6364529:G:C	G149R	1.000
19:6364530:G:A	G149D	1.000
19:6364530:G:T	G149V	1.000
19:6364541:A:C	S153R	1.000
19:6364542:G:T	S153I	1.000
19:6364543:C:A	S153R	1.000
19:6364543:C:G	S153R	1.000
19:6364616:C:G	H178D	1.000
19:6366285:G:C	A195P	1.000
19:6361894:T:A	I75N	0.999
19:6361909:T:C	L80P	0.999
19:6361915:A:T	E82V	0.999
19:6361917:C:A	R83S	0.999
19:6361918:G:C	R83P	0.999
19:6361918:G:T	R83L	0.999
19:6361921:T:A	I84N	0.999
19:6361930:T:A	V87D	0.999
19:6362462:C:A	A96D	0.999
19:6362477:C:A	A101E	0.999
19:6362486:T:A	L104H	0.999
19:6362486:T:C	L104P	0.999
19:6362488:T:C	F105L	0.999
19:6362490:C:A	F105L	0.999

dbSNP variants (sampled 300 via entrez): RS1000111925 (19:6370386 G>A), RS1000769345 (19:6359602 G>A), RS1000841963 (19:6364182 C>T), RS1000943586 (19:6369468 C>T), RS1001417400 (19:6369223 A>C), RS1001612870 (19:6367534 G>A,C), RS1001714686 (19:6362197 C>G,T), RS1001791402 (19:6362763 T>C), RS1001894233 (19:6362950 C>G,T), RS1001998929 (19:6366471 T>A), RS1002005481 (19:6368066 G>T), RS1002348187 (19:6366029 G>A,T), RS1002556743 (19:6368721 T>C), RS1002717334 (19:6363475 G>A), RS1003019031 (19:6368888 A>G)

Disease associations

OMIM: gene MIM:601119 | disease phenotypes: MIM:614129, MIM:233400

GenCC curated gene-disease

Disease	Classification	Inheritance
Perrault syndrome 3	Definitive	Autosomal recessive
Perrault syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Perrault syndrome 3	Definitive	AR

Mondo (3): Perrault syndrome 3 (MONDO:0013588), Perrault syndrome 1 (MONDO:0009300), Perrault syndrome (MONDO:0017312)

Orphanet (2): Perrault syndrome (Orphanet:2855), Perrault syndrome type 1 (Orphanet:642945)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000786	Primary amenorrhea
HP:0000815	Hypergonadotropic hypogonadism
HP:0001250	Seizure
HP:0004322	Short stature
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0010464	Streak ovary
HP:0011969	Elevated circulating luteinizing hormone level

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523305 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 880 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL4297310	DORDAVIPRONE	3	819
CHEMBL4650311	ONC-206	1	61

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — AAA ATPases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 16z [PMID: 35609303]	Activation	6.7	pEC50

ChEMBL bioactivities

212 potent at pChembl≥5 of 243 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.98	EC50	10.5	nM	CHEMBL4303616
7.92	EC50	12.02	nM	DORDAVIPRONE
7.66	EC50	21.8	nM	CHEMBL6177725
7.57	EC50	26.9	nM	CHEMBL6172967
7.52	Kd	30.3	nM	CHEMBL5572211
7.36	EC50	43.4	nM	CHEMBL6172944
7.35	EC50	44.8	nM	CHEMBL6177581
7.28	Kd	53	nM	CHEMBL5597011
7.25	EC50	56.1	nM	CHEMBL6166703
7.23	EC50	59.2	nM	CHEMBL6167082
7.20	EC50	62.8	nM	CHEMBL6173060
7.19	EC50	65.1	nM	CHEMBL6172920
7.17	EC50	67.9	nM	CHEMBL6164875
7.10	EC50	80	nM	CHEMBL5597011
7.06	Kd	87.9	nM	CHEMBL6177210
7.05	EC50	90	nM	CHEMBL5597441
7.05	EC50	90	nM	CHEMBL5596220
7.03	EC50	93	nM	CHEMBL6170047
7.00	EC50	100	nM	CHEMBL5170429
6.96	EC50	110	nM	CHEMBL5176506
6.95	EC50	113.4	nM	CHEMBL6176209
6.92	EC50	120	nM	CHEMBL5194447
6.92	EC50	120	nM	CHEMBL5287429
6.92	EC50	120	nM	CHEMBL5290620
6.92	EC50	120	nM	CHEMBL5283010
6.92	EC50	120	nM	CHEMBL5596597
6.89	EC50	130	nM	CHEMBL5173519
6.89	EC50	130	nM	CHEMBL5180553
6.89	EC50	130	nM	CHEMBL5597008
6.89	EC50	130	nM	CHEMBL5598515
6.89	EC50	130	nM	CHEMBL5275131
6.87	EC50	135	nM	CHEMBL5275131
6.85	EC50	140	nM	CHEMBL5426567
6.85	EC50	140	nM	CHEMBL5597414
6.82	EC50	150.7	nM	CHEMBL6176195
6.81	Kd	155	nM	CHEMBL5597011
6.81	EC50	156	nM	CHEMBL5287669
6.80	EC50	160	nM	CHEMBL5205960
6.75	Kd	180	nM	CHEMBL5191392
6.74	Kd	181.1	nM	CHEMBL6192038
6.72	EC50	190	nM	CHEMBL5197418
6.70	EC50	200	nM	CHEMBL5191392
6.70	EC50	200	nM	CHEMBL5572211
6.68	EC50	210	nM	CHEMBL5196310
6.66	EC50	220	nM	CHEMBL6192038
6.64	EC50	230	nM	CHEMBL5597713
6.62	EC50	240	nM	CHEMBL5598503
6.62	EC50	240	nM	CHEMBL6192577
6.58	EC50	260	nM	CHEMBL5193179
6.58	EC50	260	nM	CHEMBL5597740

PubChem BioAssay actives

141 with measured affinity, of 429 total; 50 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
N-[1-(4-chloroanilino)-1-oxopropan-2-yl]oxy-3,5-bis(trifluoromethyl)benzamide	2089290: Agonist activity at human ClpP expressed in Escherichia coli using AC-WLA-AMC as substrate measured every 5 mins for 1 hr by fluorescence based analysis	ec50	0.0105	uM
11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one	2089290: Agonist activity at human ClpP expressed in Escherichia coli using AC-WLA-AMC as substrate measured every 5 mins for 1 hr by fluorescence based analysis	ec50	0.0120	uM
1-[(3-cyanophenyl)methyl]-N-[[4-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-2H-pyridine-5-carboxamide	2089293: Binding affinity to human ClpP expressed in Escherichia coli assessed as dissociation constant by ITC method	kd	0.0303	uM
11-[(3-chlorophenyl)methyl]-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122731: Binding affinity to human recombinant N-terminal 6his/sumo tagged ClpP (57 to 277 residues) assessed as dissociation constant incubated for 30 mins by MST assay	kd	0.0530	uM
11-[(3-chlorophenyl)methyl]-7-[(4-chlorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.0900	uM
3-[[7-[(4-chlorophenyl)methyl]-8-oxo-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-11-yl]methyl]benzonitrile	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.0900	uM
11-benzyl-5-[(3-methoxyphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1000	uM
11-benzyl-5-[(2-methoxyphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1100	uM
3-[[7-[(4-chlorophenyl)methyl]-8-oxo-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-11-yl]methyl]benzonitrile	1920623: Agonist activity at human recombinant CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1200	uM
3-[[8-oxo-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-11-yl]methyl]benzonitrile	1920623: Agonist activity at human recombinant CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1200	uM
5,11-dibenzyl-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1200	uM
11-[(3-chlorophenyl)methyl]-7-[(4-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.1200	uM
1-(3-aminopropyl)-6-[(3-methylphenyl)methyl]-3-[[4-(trifluoromethyl)phenyl]methyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-2,4-dione	1920623: Agonist activity at human recombinant CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1200	uM
11-benzyl-5-[(4-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1300	uM
11-benzyl-5-(cyclohexylmethyl)-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1300	uM
11-[(3-fluorophenyl)methyl]-7-[(4-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.1300	uM
7-[(4-chlorophenyl)methyl]-11-[(3-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.1300	uM
3-[[3-[(4-chlorophenyl)methyl]-1-methyl-2,4-dioxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]methyl]benzonitrile	1920623: Agonist activity at human recombinant CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1350	uM
3-[[3-[(4-chlorophenyl)methyl]-4-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]methyl]benzonitrile	2022458: Activation of recombinant human CLpP using casein-FITC as substrate preincubated for 30 mins followed by substrate addition by spectra max i3x fluorescence based assay	ec50	0.1400	uM
11-[(3-fluorophenyl)methyl]-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.1400	uM
11-benzyl-5-[(2,4-difluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1600	uM
11-benzyl-5-[(3-bromo-4-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911139: Binding affinity to human CLpP assessed as dissociation constant by ITC method	kd	0.1800	uM
11-benzyl-5-[(2-chlorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.1900	uM
11-benzyl-5-[(4-bromo-3-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.2100	uM
11-benzyl-7-[(4-chlorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.2300	uM
11-benzyl-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.2400	uM
11-benzyl-5-[(3-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.2600	uM
7-benzyl-11-[(3-chlorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.2600	uM
11-benzyl-7-[(4-bromophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.2600	uM
11-benzyl-5-[(3-chlorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.2800	uM
11-benzyl-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.2900	uM
11-benzyl-5-[(4-chlorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3000	uM
11-benzyl-5-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3000	uM
11-benzyl-5-[(3,4-difluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3000	uM
11-benzyl-5-[(4-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3200	uM
11-[(3,4-difluorophenyl)methyl]-5-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3200	uM
7-benzyl-11-[(3-bromophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.3200	uM
11-benzyl-5-[(3-bromophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3600	uM
11-benzyl-5-(naphthalen-2-ylmethyl)-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3600	uM
11-benzyl-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.3900	uM
[4-(1,3,4-oxadiazol-2-yl)phenyl] 2-(2-ethynylbenzo[e][1]benzofuran-1-yl)acetate	1509611: Inhibition of C-terminal recombinant human ClpP expressed in Escherichia coli Rosetta2 (DE3) cells using Suc-Leu-Tyr-AMC as substrate incubated for 15 mins and measured for 90 mins by fluorescence assay	ic50	0.3900	uM
11-benzyl-5-[(3-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.3900	uM
11-benzyl-5-[(4-bromophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.4000	uM
11-benzyl-5-(2-phenylethyl)-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.4200	uM
11-benzyl-7-[(2,4-difluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.4200	uM
11-benzyl-5-[(2-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.4400	uM
(E)-N-[(2S)-3-(3,5-difluorophenyl)-1-oxo-1-[[(3R,9S,10S,13S,19S,22S,24S)-10,19,24-trimethyl-2,8,12,18,21-pentaoxo-11-oxa-1,17,20-triazatetracyclo[20.4.0.03,7.013,17]hexacosan-9-yl]amino]propan-2-yl]oct-2-enamide	2022466: Binding affinity to CLpP (unknown origin)	ec50	0.4400	uM
11-benzyl-5-(3-methylbutyl)-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.4500	uM
11-benzyl-7-[(4-fluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5-trien-8-one	2122727: Activation of human recombinant his-sumo tagged ClpP expressed in Escherichia coli BL21 (DE3) using FITC-casein as substrate preincubated for 30 mins followed by substrate addition and measured every 60 secs for 30 mins by fluorescence based microplate reader analysis	ec50	0.4800	uM
11-benzyl-13,13-difluoro-5-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),6-dien-8-one	1911131: Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay	ec50	0.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
lead acetate	increases abundance, increases expression, affects reaction	1
trichostatin A	affects expression	1
arsenite	increases reaction, affects binding	1
afimoxifene	affects response to substance	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	affects cotreatment, decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
10-(octyloxy)decyl-2-(trimethylammonium)ethyl phosphate	decreases expression	1
bisphenol AF	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Citrinin	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects reaction, increases abundance, increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

96 unique, capped per target: 96 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4305800	Binding	Inhibition of C-terminal recombinant human ClpP (57 to 277 amino acids) expressed in Escherichia coli Rosetta2 cells using Suc-Leu-Tyr-AMC as substrate incubated for 1 hr and measured for 90 mins by fluorescence assay	De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX. — J Med Chem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1M1	Abcam K-562 CLPP KO	Cancer cell line	Female
CVCL_D2IL	Abcam Raji CLPP KO	Cancer cell line	Male
CVCL_E1TW	HAP1 CLPP (-) 2	Cancer cell line	Male
CVCL_E1TX	HAP1 CLPP (-) 3	Cancer cell line	Male
CVCL_UQ33	Abcam Jurkat CLPP KO	Cancer cell line	Male
CVCL_XM85	HAP1 CLPP (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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