CAPN1

Summary

CAPN1 (calpain 1, HGNC:1476) is a protein-coding gene on chromosome 11q13.1, encoding Calpain-1 catalytic subunit (P07384). Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.

The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 823 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive spastic paraplegia type 76 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 393 total — 35 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005186

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1476
Approved symbol	CAPN1
Name	calpain 1
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	muCANP, muCL, CANP, CANPL1
Ensembl gene	ENSG00000014216
Ensembl biotype	protein_coding
OMIM	114220
Entrez	823

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 16 protein_coding, 8 retained_intron, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000279247, ENST00000524773, ENST00000525013, ENST00000526468, ENST00000526954, ENST00000526966, ENST00000527189, ENST00000527323, ENST00000527469, ENST00000527699, ENST00000527739, ENST00000527887, ENST00000527897, ENST00000528165, ENST00000528396, ENST00000528739, ENST00000529133, ENST00000530442, ENST00000530495, ENST00000530567, ENST00000531068, ENST00000532285, ENST00000533079, ENST00000533129, ENST00000533704, ENST00000533820, ENST00000533909, ENST00000534373, ENST00000903824

RefSeq mRNA: 3 — MANE Select: NM_005186 NM_001198868, NM_001198869, NM_005186

CCDS: CCDS44644

Canonical transcript exons

ENST00000279247 — 22 exons

Exon	Start	End
ENSE00001119924	65187955	65188040
ENSE00001192571	65206463	65206674
ENSE00001192601	65186170	65186338
ENSE00001273768	65209323	65209387
ENSE00001273856	65185917	65186050
ENSE00001535113	65181928	65182013
ENSE00003460533	65209849	65209917
ENSE00003475253	65182701	65182968
ENSE00003483377	65183128	65183197
ENSE00003489982	65205710	65205721
ENSE00003515030	65204683	65204858
ENSE00003523527	65210814	65210872
ENSE00003561095	65210018	65210096
ENSE00003577853	65210336	65210452
ENSE00003585718	65188414	65188488
ENSE00003599360	65208205	65208262
ENSE00003638893	65208055	65208120
ENSE00003648977	65188586	65188746
ENSE00003678096	65206780	65206819
ENSE00003688934	65187215	65187298
ENSE00003787895	65183474	65183592
ENSE00003902641	65211260	65212006

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 99.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 77.5824 / max 635.2292, expressed in 1825 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115039	67.8508	1824
115036	4.3279	1658
115038	1.7434	1106
115035	1.0108	660
115041	0.8812	362
115037	0.7139	408
115040	0.3694	203
115045	0.2111	78
115049	0.1909	47
115043	0.1198	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.31	gold quality
endometrium epithelium	UBERON:0004811	99.02	gold quality
esophagus mucosa	UBERON:0002469	98.81	gold quality
mucosa of transverse colon	UBERON:0004991	98.58	gold quality
skin of abdomen	UBERON:0001416	98.41	gold quality
skin of leg	UBERON:0001511	98.41	gold quality
minor salivary gland	UBERON:0001830	98.38	gold quality
right uterine tube	UBERON:0001302	98.22	gold quality
metanephros cortex	UBERON:0010533	98.12	gold quality
right lobe of thyroid gland	UBERON:0001119	98.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.94	gold quality
left lobe of thyroid gland	UBERON:0001120	97.89	gold quality
esophagus	UBERON:0001043	97.77	gold quality
mouth mucosa	UBERON:0003729	97.63	gold quality
transverse colon	UBERON:0001157	97.52	gold quality
gall bladder	UBERON:0002110	97.52	gold quality
ectocervix	UBERON:0012249	97.44	gold quality
mucosa of stomach	UBERON:0001199	97.37	gold quality
endocervix	UBERON:0000458	97.29	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.28	gold quality
body of pancreas	UBERON:0001150	97.24	gold quality
vagina	UBERON:0000996	97.21	gold quality
pharyngeal mucosa	UBERON:0000355	97.17	gold quality
granulocyte	CL:0000094	97.11	gold quality
body of stomach	UBERON:0001161	97.10	gold quality
thyroid gland	UBERON:0002046	97.06	gold quality
upper lobe of left lung	UBERON:0008952	96.89	gold quality
lower esophagus	UBERON:0013473	96.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.53	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

41 targeting CAPN1, 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-6876-5P	100.00	67.68	2126
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-4297	98.77	66.95	2013

Literature-anchored findings (GeneRIF, showing 40)

• Calpain (mu-calpain) is a signal transducer and activator of transcription (STAT) 3 and STAT5 protease. (PMID:11861304)
• cleaves SNAP-23 in activated platelets (PMID:12121992)
• investigates whether E-cadherin is a substrate for calpain and whether calpain-dependent proteolysis was associated with prostate cancer progression (PMID:12393869)
• calpastatin and calpain-1 represent critical proximal elements in a cascade of pro-apoptotic events leading to Bax, mitochondria, and caspase-3 activation (PMID:14612448)
• mu-calpain and m-calpain expression may be compromised in the anterior vaginal wall of women with uterovaginal prolapse (PMID:14980313)
• platelet FXIII and calpain have roles in regulating integrin alpha(IIb)beta3 adhesive function (PMID:15131115)
• calpain I and II, calpastatin, and the regulatory subunit localize to the cytosolic surface of the endoplasmic reticulum and Golgi apparatus membranes (PMID:15302874)
• nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced cell migration and invasion may occur, at least in part, through a novel mechanism involving phosphorylation of calpains that leads to their activation and secretion (PMID:15471877)
• Epidermal growth factor activates m-calpain, which causes apoptosis of HaCaT keratinocytes (PMID:15488707)
• Both precursor and mature forms of recombinant AIF were cleaved near the amino terminus by calpain I in vitro (PMID:15590628)
• Mu-calpain is activated in human endometrial cells during hypoxia and that subsequent cleavage of the integrin beta3 cytoplasmic domain may give some adverse effects to the function of human endometrium (PMID:15663601)
• mu-calpain, is a potential candidate for alpha-secretase in the regulated Alzheimer’s beta-amyloid precursor protein alpha-processing (PMID:15809056)
• These observations indicate that calpain is activated and reacts with alpha-fodrin as a substrate at the sarcolemma, and plays a key role in modulating sarcolemmal proteins to adapt to the specific conditions in each myopathy (PMID:15948206)
• Immunohistochemistry of fixed, permeabilized oocytes exhibit localization of calpain mu isoform to the cortical region of the oocyte, as well as the cytosol. (PMID:15950654)
• calpains may play a physiological role in the regulation of p73 protein stability (PMID:15975558)
• the time- and concentration-dependent changes in [Ca2+]i that occurred during concentric exercise fall near but below the level necessary to cause autolysis of calpains in vivo (PMID:16107503)
• The activation of calcineurin by calpain I in the brain of patients with Alzheimer’s disease is reported. (PMID:16150694)
• a novel role for PKCiota as a nicotine-activated, physiological calpain kinase that directly phosphorylates and activates calpains. (PMID:16361262)
• beside its known effect on general muscle protein degradation, calpain contributes to Duchenne muscular dystrophy pathology by specifically degrading the compensatory protein utrophin (PMID:16598790)
• Knockdown of mu-calpain decreased the proteolytic products of filamin and talin suggesting that their proteolysis could be one of the key mechanisms by which mu-calpain regulates cell migration. (PMID:16697376)
• In vitro membrane binding of mu-calpain is due to the exposed hydrophobic surface of the active conformation and does not reduce the Ca2+ requirement for activation. (PMID:16740134)
• Acyl coenzyme A-binding protein has a role in augmenting bid-induced mitochondrial damage and cell death by activating mu-calpain (PMID:16908521)
• phosphorylation of Thr(138) predominantly defines the susceptibility of p35 to calpain-dependent cleavage and dephosphorylation of this site is a critical determinant of Cdk5-p25-induced cell death associated with neurodegeneration (PMID:17121855)
• We have solved the structures of human calpain 1 and calpain 9 protease cores ; both structures have clear implications for the function of non-catalytic domains of full-length calpains in the calcium-mediated activation of the enzyme. (PMID:17157313)
• Results suggest that calpains are involved in hypoxia-induced necrotic cell death, and that the inhibition of calpain switches hypoxia-induced cell death to apoptotic cell death without affecting cell viability. (PMID:17195093)
• association between mu- and m-calpain, the specific inhibitor calpastatin, and axonal injury in post mortem brain tissue from patients who died from severe malaria (PMID:17359359)
• Nitric oxide-induced motility in osteoclasts requires regulated Ca(2+) release, which activates mu-calpain. This occurs via the Ins(1,4,5)P(3)R1. (PMID:17690304)
• These findings pinpoint calpain-1 as a regulator of Frizzled-7 turnover at the plasma membrane and reveal a link between Frizzled-7 cleavage and its activity. (PMID:17716656)
• Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients. (PMID:17765980)
• In patients with Alzheimer disease, over-activation of calpain because of calcium dysregulation causes increased degradation and thus decreased activity of PKA, which, in turn, contributes to down-regulation of CREB and impaired cognition and memory. (PMID:17908236)
• Calpain emerges as a central player in E7-mediated degradation of Rb (PMID:17977825)
• both calpain 1 and calpain 2 are essential for the replication of EV1 RNA. (PMID:18032503)
• calpain 1 N-terminus is a mitochondrial targeting sequence (PMID:18070881)
• platelets from patients with type 2 diabetes mellitus, were found to have enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA-2), elevated platelet [Ca2+]i, and activation of mu-calpain. (PMID:18071073)
• Protein adducts of iso[4]levuglandin E2 (iso[4]LGE2), a highly reactive product of free radical-induced lipid oxidation, accumulate in human glaucomatous trabecular meshwork (TM) but not in controls. (PMID:18085799)
• The activity of calpain in human peripheral blood lymphocytes, was estimated by assessing the levels of limited proteolysis of calpastatin. (PMID:18165173)
• The above suggests that cleavage of DAT by calpain may significantly modify dopamine homeostasis under pathological or physiological conditions. (PMID:18468730)
• genetically determined IL-1alpha levels may modulate transcription of calpain and calpastatin. (PMID:18498295)
• Reduced eNOS protein levels were accompanied by an increase in intracellular Ca(2+), augmented production of reactive oxygen species (ROS) and induction of Ca(2+)-dependent calpain activity. (PMID:18624772)
• These results demonstrate calpain involvement in proteasome inhibitor-induced AR breakdown, and suggest that AR degradation is intrinsic to the induction of apoptosis in prostate cancer cells. (PMID:18726991)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	capn1	ENSDARG00000045199
danio_rerio	CAPN1	ENSDARG00000055338
mus_musculus	Capn1	ENSMUSG00000024942
rattus_norvegicus	Capn1	ENSRNOG00000020935
caenorhabditis_elegans		WBGENE00000542
caenorhabditis_elegans	clp-3	WBGENE00000544
caenorhabditis_elegans		WBGENE00000546
caenorhabditis_elegans		WBGENE00000547
caenorhabditis_elegans		WBGENE00006606
caenorhabditis_elegans	clp-8	WBGENE00009695
caenorhabditis_elegans	clpr-3	WBGENE00010417
caenorhabditis_elegans	clpr-1	WBGENE00012233
caenorhabditis_elegans	clpr-3	WBGENE00013184

Paralogs (20): SRI (ENSG00000075142), CAPN6 (ENSG00000077274), CAPN3 (ENSG00000092529), CAPN15 (ENSG00000103326), GCA (ENSG00000115271), ADGB (ENSG00000118492), CAPNS1 (ENSG00000126247), CAPN7 (ENSG00000131375), CAPN9 (ENSG00000135773), CAPN11 (ENSG00000137225), CAPN10 (ENSG00000142330), CAPN5 (ENSG00000149260), PEF1 (ENSG00000162517), CAPN2 (ENSG00000162909), CAPN13 (ENSG00000162949), CAPN12 (ENSG00000182472), CAPN8 (ENSG00000203697), CAPN14 (ENSG00000214711), PDCD6 (ENSG00000249915), CAPNS2 (ENSG00000256812)

Protein

Protein identifiers

Calpain-1 catalytic subunit — P07384 (reviewed: P07384)

Alternative names: Calcium-activated neutral proteinase 1, Calpain mu-type, Calpain-1 large subunit, Cell proliferation-inducing gene 30 protein, Micromolar-calpain

All UniProt accessions (11): P07384, E9PIA9, E9PJA6, E9PJJ3, E9PL37, E9PLC9, E9PLX0, E9PMC6, E9PQB3, E9PRM1, E9PSA6

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves CTBP1 at ‘Asn-375’, ‘Gly-387’ and ‘His-409’. Cleaves and activates caspase-7 (CASP7).

Subunit / interactions. Forms a heterodimer with a small (regulatory) subunit CAPNS1.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Undergoes calcium-induced successive autoproteolytic cleavages that generate a membrane-bound 78 kDa active form and an intracellular 75 kDa active form. Calpastatin reduces with high efficiency the transition from 78 kDa to 75 kDa calpain forms.

Disease relevance. Spastic paraplegia 76, autosomal recessive (SPG76) [MIM:616907] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by micromolar concentrations of calcium and inhibited by calpastatin.

Cofactor. Binds 4 Ca(2+) ions.

Similarity. Belongs to the peptidase C2 family.

RefSeq proteins (3): NP_001185797, NP_001185798, NP_005177* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR001300	Peptidase_C2_calpain_cat	Domain
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR022682	Calpain_domain_III	Domain
IPR022683	Calpain_III	Domain
IPR022684	Calpain_cysteine_protease	Family
IPR033883	C2_III	Domain
IPR036213	Calpain_III_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily

Pfam: PF00648, PF01067, PF13833

Enzyme classification (BRENDA):

• EC 3.4.22.52 — calpain-1 (BRENDA: 24 organisms, 175 substrates, 258 inhibitors, 23 Km, 11 kcat entries)
• EC 3.4.22.53 — calpain-2 (BRENDA: 21 organisms, 189 substrates, 162 inhibitors, 17 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
SUCCINYL-LEU-TYR-7-AMIDO-4-METHYLCOUMARIN	0.431–3.18	4
SUCCINYL-BOVINE SERUM ALBUMIN	0.002–2	2
SUCCINYL-CASEIN	0.0081	2
SUCCINYL-INSULIN B	0.284–283.5	2
SUCCINYL-PROTAMINE	0.063–63	2
SUCCINYL-LEU-LEU-VAL-TYR-7-AMIDO-4-METHYLCOUMARI	0.459–0.461	2
SUCCINYL-LEU-MET-7-AMIDO-4-METHYLCOUMARIN	4.66–4.68	2
T-BUTYLOXYCARBONYL-VAL-LEU-LYS-7-AMIDO-4-METHYLC	8.11–8.12	2
2-AMINOBENZOYL-EVYGMMY(3-NO2)-OH	0.043	1
4,4-DIFLUORO-5,7-DIMETHYL-4-BORA-31,4A-DIAZA-S-I	0.0007	1
CASEIN	0.053	1
FLUORESCIN THIOCARBAMOYL-LABELED CASEIN	0.0131	1
FODRIN	0.0001	1
K-(5(6)-CARBOXYFLUORESCEIN)-EVYGMMK(4-(4-DIMETHY	0.0046	1
N-BENZYLOXYCARBONYL-L-LEU-L-ARG-4-METHOXY-2-NAPH	0.37	1

UniProt features (68 total): helix 17, binding site 15, strand 13, domain 5, sequence variant 5, active site 3, region of interest 3, site 2, modified residue 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7W7O	X-RAY DIFFRACTION	1.59
7X79	X-RAY DIFFRACTION	1.8
8GX3	X-RAY DIFFRACTION	1.99
1ZCM	X-RAY DIFFRACTION	2
2ARY	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07384-F1	90.03	0.68

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 (5): 115; 272; 296; 15–16 (cleavage; for 78 kda form); 27–28 (cleavage; for 75 kda form)

Ligand- & substrate-binding residues (15): 109; 114; 316; 318; 323; 598; 600; 602; 604; 609; 628; 630 …

Post-translational modifications (2): 2, 354

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-6798695	Neutrophil degranulation
R-HSA-6809371	Formation of the cornified envelope
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models
R-HSA-1266738	Developmental Biology
R-HSA-1474244	Extracellular matrix organization
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-6805567	Keratinization
R-HSA-8863678	Neurodegenerative Diseases
R-HSA-9645723	Diseases of programmed cell death
R-HSA-9734009	Defective Intrinsic Pathway for Apoptosis

MSigDB gene sets: 244 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_MAMMARY_GLAND_MORPHOGENESIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_GLAND_MORPHOGENESIS, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORI_IMMATURE_B_LYMPHOCYTE_UP, AAAYRNCTG_UNKNOWN, chr11q13, GOBP_MACROAUTOPHAGY, PATIL_LIVER_CANCER, GTGCCTT_MIR506, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GATA3_01

GO Biological Process (8): proteolysis (GO:0006508), positive regulation of cell population proliferation (GO:0008284), regulation of macroautophagy (GO:0016241), receptor catabolic process (GO:0032801), regulation of catalytic activity (GO:0050790), mammary gland involution (GO:0060056), self proteolysis (GO:0097264), NMDA selective glutamate receptor signaling pathway (GO:0098989)

GO Molecular Function (7): calcium-dependent cysteine-type endopeptidase activity (GO:0004198), calcium ion binding (GO:0005509), peptidase activity (GO:0008233), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (12): cornified envelope (GO:0001533), extracellular region (GO:0005576), cytoplasm (GO:0005737), mitochondrion (GO:0005739), lysosome (GO:0005764), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), extracellular exosome (GO:0070062), calpain complex (GO:0110158), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Extracellular matrix organization	1
Innate Immune System	1
Keratinization	1
Neurodegenerative Diseases	1
Immune System	1
Developmental Biology	1
Defective Intrinsic Pathway for Apoptosis	1
Disease	1
Diseases of programmed cell death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
catalytic activity	2
protein metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of autophagy	1
macroautophagy	1
macromolecule catabolic process	1
receptor metabolic process	1
regulation of molecular function	1
tissue remodeling	1
mammary gland morphogenesis	1
proteolysis	1
NMDA glutamate receptor activity	1
ionotropic glutamate receptor signaling pathway	1
cysteine-type endopeptidase activity	1
metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
binding	1
peptidase activity	1
cation binding	1
plasma membrane	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
lytic vacuole	1
membrane	1
cell periphery	1
cell-substrate junction	1
extracellular vesicle	1
caspase complex	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

2295 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAPN1	CAPNS1	P04632	981
CAPN1	CAST	P20810	969
CAPN1	AHNAK	Q09666	791
CAPN1	PYGM	P11217	786
CAPN1	MAP3K11	Q16584	771
CAPN1	PLCB3	Q01970	769
CAPN1	CHRM1	P11229	768
CAPN1	COX8A	P10176	766
CAPN1	SF1	Q15637	766
CAPN1	FKBP2	P26885	765
CAPN1	FTH1	P02794	764
CAPN1	ROM1	Q03395	764
CAPN1	FOSL1	P15407	763
CAPN1	SCGB1A1	P11684	762
CAPN1	MARK2	Q7KZI7	762

IntAct

99 interactions, top by confidence:

A	B	Type	Score
CAPN1	CAPNS1	psi-mi:“MI:0914”(association)	0.840
CAPN1	CAPNS1	psi-mi:“MI:0194”(cleavage reaction)	0.840
CAPN1	CAPNS1	psi-mi:“MI:0915”(physical association)	0.840
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PTPN1	CAPN1	psi-mi:“MI:0414”(enzymatic reaction)	0.680
CAPNS2	CAPN1	psi-mi:“MI:0914”(association)	0.640
CFTR	CAPN1	psi-mi:“MI:0915”(physical association)	0.600
BAD	CAPN1	psi-mi:“MI:0915”(physical association)	0.560
CAPN1	CMPK1	psi-mi:“MI:0915”(physical association)	0.560
CAPN1	OPTN	psi-mi:“MI:0915”(physical association)	0.560
APP	CAPN1	psi-mi:“MI:0915”(physical association)	0.560
MAP4	CAPN1	psi-mi:“MI:0915”(physical association)	0.560
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
CAPN8	CAPN1	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
KNG1	CTSV	psi-mi:“MI:0914”(association)	0.530

BioGRID (255): CAPN1 (Affinity Capture-Western), ATG5 (Biochemical Activity), CAPN1 (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), ATP6V1A (Co-fractionation), CAPN1 (Co-fractionation), CAPN1 (Co-fractionation), EIF2A (Co-fractionation), HNRNPR (Co-fractionation), NIT1 (Co-fractionation), SKIV2L2 (Co-fractionation), SYNCRIP (Co-fractionation), CAPN1 (Affinity Capture-MS)

ESM2 similar proteins: A2YQ56, A3QRX8, A6NHC0, O08529, O14815, O35350, O35920, P00789, P07384, P17569, P17655, P20807, P35750, P36776, P39866, P93648, P93655, P97571, Q07009, Q07093, Q11002, Q27970, Q27971, Q4KM30, Q59HJ6, Q5NVS7, Q5PQ09, Q5R456, Q5XIT6, Q5ZIV7, Q641Z6, Q69UZ3, Q6DC39, Q6GLM5, Q6ICB0, Q78EJ9, Q8CGK3, Q8X1T0, Q91VA3, Q92178

Diamond homologs: A6NHC0, A8MX76, G3V7W1, O08529, O08688, O14815, O15484, O23184, O35350, O35646, O35920, O75808, O88456, O88501, P00789, P04574, P04632, P05044, P06813, P06814, P06815, P07384, P13135, P16259, P17655, P20807, P27398, P27730, P28676, P30626, P34308, P35750, P43367, P43368, P51186, P97571, Q07009, Q11002, Q22036, Q27970

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
calcium(2+)	“up-regulates activity”	CAPN1	“chemical activation”
CAPN1	“up-regulates activity”	CDK5/CDK5R1	cleavage
CAST	“down-regulates activity”	CAPN1	binding
CAPN1	“up-regulates activity”	CDK5R1	cleavage
CAPN1	“down-regulates activity”	MAPT	cleavage
CAPN1	“up-regulates activity”	GSK3A	cleavage
CAPN1	“up-regulates activity”	GSK3B	cleavage
CAPN1	“up-regulates activity”	F2R	cleavage
CAPN1	“down-regulates activity”	F2R	cleavage
CAPN1	“down-regulates activity”	F2RL1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	8	7.7×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	10
Uncertain significance	161
Likely benign	110
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1338393	NM_005186.4(CAPN1):c.843+1G>C	Pathogenic
1436890	NM_005186.4(CAPN1):c.671G>A (p.Trp224Ter)	Pathogenic
1802257	NM_005186.4(CAPN1):c.181_182insC (p.Phe61fs)	Pathogenic
2135435	NM_005186.4(CAPN1):c.910_926dup (p.Asp309fs)	Pathogenic
225765	NM_005186.4(CAPN1):c.884G>C (p.Arg295Pro)	Pathogenic
225766	NM_005186.4(CAPN1):c.1579C>T (p.Gln527Ter)	Pathogenic
225767	NM_005186.4(CAPN1):c.407del (p.Pro136fs)	Pathogenic
2570800	NM_005186.4(CAPN1):c.894G>A (p.Trp298Ter)	Pathogenic
2570801	NM_005186.4(CAPN1):c.1567G>T (p.Glu523Ter)	Pathogenic
2691341	NC_000011.9:g.(64956218_64972153)_(64974291_64975525)del	Pathogenic
2829391	NM_005186.4(CAPN1):c.920G>A (p.Trp307Ter)	Pathogenic
3389204	NM_005186.4(CAPN1):c.415C>T (p.Gln139Ter)	Pathogenic
3721061	NM_005186.4(CAPN1):c.1142C>T (p.Ala381Val)	Pathogenic
3722173	NM_005186.4(CAPN1):c.147C>A (p.Cys49Ter)	Pathogenic
4294014	NM_005186.4(CAPN1):c.268-1G>T	Pathogenic
4681374	NM_005186.4(CAPN1):c.268-2A>G	Pathogenic
4703719	NM_005186.4(CAPN1):c.2017_2023del (p.Asp673fs)	Pathogenic
4803277	NM_005186.4(CAPN1):c.1161C>G (p.Tyr387Ter)	Pathogenic
4847518	NC_000011.9:g.(64955512_64955884)_(64956218_64972153)del	Pathogenic
617483	NM_005186.4(CAPN1):c.338-1G>A	Pathogenic
802686	NM_005186.4(CAPN1):c.618_619del (p.Gly208fs)	Pathogenic
802687	NM_005186.4(CAPN1):c.1176G>A (p.Trp392Ter)	Pathogenic
817644	NM_005186.4(CAPN1):c.188dup (p.Val64fs)	Pathogenic
986744	NM_005186.4(CAPN1):c.254G>A (p.Trp85Ter)	Pathogenic
986745	NM_005186.4(CAPN1):c.623G>A (p.Gly208Asp)	Pathogenic
986748	NM_005186.4(CAPN1):c.1165+1G>A	Pathogenic
986749	NM_005186.4(CAPN1):c.1341G>C (p.Glu447Asp)	Pathogenic
986750	NM_005186.4(CAPN1):c.1418_1419del (p.Arg473fs)	Pathogenic
986751	NM_005186.4(CAPN1):c.1697dup (p.Leu566fs)	Pathogenic
987184	NM_005186.4(CAPN1):c.759+1G>T	Pathogenic

SpliceAI

3641 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65182529:G:GT	donor_gain	1.0000
11:65182700:GGAT:G	acceptor_gain	1.0000
11:65182954:TGG:T	donor_gain	1.0000
11:65182956:G:GT	donor_gain	1.0000
11:65182966:ACGGT:A	donor_loss	1.0000
11:65182968:GGT:G	donor_loss	1.0000
11:65182969:G:C	donor_loss	1.0000
11:65182969:G:GG	donor_gain	1.0000
11:65182970:T:A	donor_loss	1.0000
11:65183470:CCAG:C	acceptor_loss	1.0000
11:65183472:A:AG	acceptor_gain	1.0000
11:65183472:AG:A	acceptor_gain	1.0000
11:65183472:AGG:A	acceptor_gain	1.0000
11:65183472:AGGG:A	acceptor_gain	1.0000
11:65183473:G:GA	acceptor_gain	1.0000
11:65183473:GG:G	acceptor_gain	1.0000
11:65183473:GGG:G	acceptor_gain	1.0000
11:65183473:GGGG:G	acceptor_gain	1.0000
11:65183473:GGGGA:G	acceptor_gain	1.0000
11:65183589:CCAGG:C	donor_loss	1.0000
11:65183591:AGG:A	donor_loss	1.0000
11:65183594:T:G	donor_loss	1.0000
11:65185911:CCACA:C	acceptor_loss	1.0000
11:65185914:CAGCT:C	acceptor_loss	1.0000
11:65185915:A:AG	acceptor_gain	1.0000
11:65185915:AGCT:A	acceptor_gain	1.0000
11:65185915:AGCTG:A	acceptor_loss	1.0000
11:65185916:G:GT	acceptor_gain	1.0000
11:65185916:GC:G	acceptor_gain	1.0000
11:65185916:GCT:G	acceptor_gain	1.0000

AlphaMissense

4696 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65182954:T:A	W85R	1.000
11:65182954:T:C	W85R	1.000
11:65183187:G:C	Q109H	1.000
11:65183187:G:T	Q109H	1.000
11:65183188:G:A	G110R	1.000
11:65183188:G:C	G110R	1.000
11:65183197:G:T	G113W	1.000
11:65183474:G:A	G113E	1.000
11:65183474:G:T	G113V	1.000
11:65183479:T:C	C115R	1.000
11:65183480:G:A	C115Y	1.000
11:65183481:C:G	C115W	1.000
11:65183482:T:A	W116R	1.000
11:65183482:T:C	W116R	1.000
11:65183484:G:C	W116C	1.000
11:65183484:G:T	W116C	1.000
11:65185935:T:A	W159R	1.000
11:65185935:T:C	W159R	1.000
11:65186019:T:A	W187R	1.000
11:65186019:T:C	W187R	1.000
11:65186201:G:C	G208R	1.000
11:65186202:G:A	G208D	1.000
11:65186216:G:C	G213R	1.000
11:65187258:T:C	L268S	1.000
11:65187269:C:A	H272N	1.000
11:65187269:C:G	H272D	1.000
11:65187271:T:A	H272Q	1.000
11:65187271:T:G	H272Q	1.000
11:65187275:T:C	Y274H	1.000
11:65187275:T:G	Y274D	1.000

dbSNP variants (sampled 300 via entrez): RS1000190867 (11:65188203 G>A,T), RS1000227036 (11:65199902 T>C), RS1000235338 (11:65201092 C>T), RS1000414801 (11:65203033 G>A,C), RS1000628039 (11:65188308 C>T), RS1000681169 (11:65193448 A>C), RS1000790318 (11:65181848 G>A), RS1000884776 (11:65200763 G>A), RS1000904206 (11:65207921 A>C,G,T), RS1000933530 (11:65186836 A>G), RS1000942826 (11:65202500 T>C), RS1001035299 (11:65195553 T>G), RS1001148762 (11:65201111 A>G,T), RS1001226333 (11:65194832 C>T), RS1001370981 (11:65186920 G>C)

Disease associations

OMIM: gene MIM:114220 | disease phenotypes: MIM:616907, MIM:604360

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive spastic paraplegia type 76	Strong	Autosomal recessive

Mondo (2): autosomal recessive spastic paraplegia type 76 (MONDO:0014827), hereditary spastic paraplegia 11 (MONDO:0011445)

Orphanet (2): Autosomal recessive spastic paraplegia type 76 (Orphanet:488594), Autosomal recessive spastic paraplegia type 11 (Orphanet:2822)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000020	Urinary incontinence
HP:0000496	Abnormality of eye movement
HP:0000639	Nystagmus
HP:0001251	Ataxia
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002141	Gait imbalance
HP:0002395	Lower limb hyperreflexia
HP:0002497	Spastic ataxia
HP:0002505	Loss of ambulation
HP:0002650	Scoliosis
HP:0002936	Distal sensory impairment
HP:0003202	Skeletal muscle atrophy
HP:0003390	Sensory axonal neuropathy
HP:0003487	Babinski sign
HP:0003621	Juvenile onset
HP:0006855	Cerebellar vermis atrophy
HP:0006986	Upper limb spasticity
HP:0007340	Lower limb muscle weakness
HP:0007350	Upper limb hyperreflexia
HP:0008081	Pes valgus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008972_190	Urate levels	1.000000e-23

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2111357 (PROTEIN COMPLEX), CHEMBL3038466 (PROTEIN FAMILY), CHEMBL3891 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 723 (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
CHEMBL63440	ALOXISTATIN	2	723

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C2: Calpain

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
calpeptin	Inhibition	8.3	pIC50
mercaptoacrylate inhibitor of calpain 1	Inhibition	8.22	pIC50
compound 4b [PMID: 20690647]	Inhibition	7.64	pKi
GC-376	Inhibition	7.13	pIC50
mitucapistat	Inhibition	6.77	pIC50
UAWJ9-36-3	Inhibition	4.7	pIC50

Binding affinities (BindingDB)

34 measured of 69 human assays (69 total across all organisms); most potent 34 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S,3S)-3-[[(2S)-1-[[1-(4-fluorophenyl)triazol-4-yl]methylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	30 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[1-(4-bromophenyl)triazol-4-yl]methylamino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	40 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-4-methyl-1-oxo-1-[[1-(4-sulfamoylphenyl)triazol-4-yl]methylamino]pentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	50 nM	US-9403843: Cysteine protease inhibitors and uses thereof
benzyl N-[(1S)-2-methyl-1-[(1-oxo-3-phenylpropan-2-yl)carbamoyl]propyl]carbamate	IC50	100 nM
(2S)-3-[[(2S)-1-[4-[5-(dithiolan-3-yl)pentanoylamino]butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S)-3-[[(2S)-1-[4-(diaminomethylideneamino)butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S)-3-[[(2S)-1-[4-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S)-3-[[(2S)-1-[4-[(4-fluorophenyl)sulfonylamino]butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[4-[(4-fluorophenyl)sulfonylamino]butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-(2,6-difluoroanilino)-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-anilino-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2R,3R)-3-[[(2S)-1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[1-(4-fluorophenyl)triazol-4-yl]methylamino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[4-(4-ethynylphenyl)-1,3-thiazol-2-yl]amino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	100 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[4-[5-(dithiolan-3-yl)pentanoylamino]butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	150 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2R,3R)-3-[[(2S)-1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	175 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-methylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	200 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]-3-(1-methylimidazol-4-yl)-1-oxopropan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	225 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	250 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-4-methyl-1-oxo-1-(prop-2-ynylamino)pentan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	275 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[1-(4-nitrophenyl)triazol-4-yl]methylamino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	300 nM	US-9403843: Cysteine protease inhibitors and uses thereof
benzyl N-[1-[(4-fluoro-3-oxo-1-phenylbutan-2-yl)amino]-1-oxo-3-phenylpropan-2-yl]carbamate	IC50	397 nM
(2S,3S)-3-[[(2S)-1-[[1-(1,3-benzodioxol-5-yl)triazol-4-yl]methylamino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	400 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3R)-3-[[(2S)-1-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	535 nM	US-9403843: Cysteine protease inhibitors and uses thereof
N-[(2S)-1-(4-acetamidobutylamino)-4-methyl-1-oxopentan-2-yl]-3-phenyloxirane-2-carboxamide	IC50	1000 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[1-[4-[(4-fluorophenyl)sulfonylamino]butylcarbamoyl]cyclohexyl]carbamoyl]oxirane-2-carboxylic acid	IC50	1000 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-oxo-1-[(1-phenyltriazol-4-yl)methylamino]-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	1000 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-oxo-1-[[1-(4-piperidin-1-ylsulfonylphenyl)triazol-4-yl]methylamino]-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	1500 nM	US-9403843: Cysteine protease inhibitors and uses thereof
ethyl (2S,3S)-3-[[(2S)-1-anilino-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylate	IC50	2500 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-anilino-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	2500 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-anilino-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	5000 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-1-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]-3-(3-methylimidazol-4-yl)-1-oxopropan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	5000 nM	US-9403843: Cysteine protease inhibitors and uses thereof
(2S,3S)-3-[[(2S)-3-(1H-imidazol-5-yl)-1-oxo-1-(2,4,6-trimethylanilino)propan-2-yl]carbamoyl]oxirane-2-carboxylic acid	IC50	5000 nM	US-9403843: Cysteine protease inhibitors and uses thereof

ChEMBL bioactivities

830 potent at pChembl≥5 of 886 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	Ki	0.2	nM	CHEMBL5723369
8.70	Ki	2	nM	CHEMBL89100
8.68	IC50	2.1	nM	CHEMBL8651
8.52	IC50	3	nM	CHEMBL4073900
8.47	Ki	3.4	nM	CHEMBL314442
8.40	IC50	4	nM	CHEMBL151521
8.40	IC50	4	nM	CHEMBL150600
8.40	Ki	4	nM	CHEMBL91991
8.31	IC50	4.9	nM	CHEMBL203568
8.30	IC50	5	nM	CHEMBL357595
8.30	IC50	5	nM	CALPEPTIN
8.30	IC50	5	nM	CHEMBL117553
8.30	IC50	5	nM	CHEMBL8378
8.22	IC50	6	nM	CHEMBL345338
8.22	IC50	6	nM	CHEMBL326161
8.22	IC50	6	nM	CHEMBL299750
8.22	Ki	6	nM	CHEMBL92114
8.22	Ki	6	nM	CHEMBL280587
8.15	IC50	7	nM	CHEMBL423222
8.15	IC50	7	nM	CHEMBL118688
8.15	IC50	7	nM	CHEMBL269384
8.15	Ki	7	nM	CALPEPTIN
8.15	IC50	7	nM	CHEMBL8605
8.15	IC50	7	nM	CHEMBL127231
8.12	IC50	7.5	nM	CHEMBL288365
8.12	IC50	7.5	nM	CHEMBL168471
8.10	IC50	8	nM	CHEMBL347742
8.10	IC50	8	nM	CHEMBL356841
8.10	IC50	8	nM	CHEMBL345337
8.10	IC50	8	nM	CHEMBL204883
8.10	IC50	8	nM	CHEMBL269333
8.10	Ki	8	nM	CHEMBL4092996
8.10	Ki	8	nM	CHEMBL315636
8.10	Ki	8	nM	CHEMBL286722
8.10	Ki	8	nM	CHEMBL305715
8.08	Ki	8.4	nM	CHEMBL310855
8.07	Ki	8.5	nM	CHEMBL117023
8.05	Ki	9	nM	CHEMBL407974
8.05	Ki	9	nM	CHEMBL4167219
8.05	Ki	9	nM	CHEMBL90661
8.05	Ki	9	nM	CHEMBL88484
8.05	Ki	9	nM	CHEMBL89008
8.05	Ki	9	nM	CHEMBL89766
8.00	IC50	10	nM	CHEMBL151536
8.00	IC50	10	nM	CHEMBL341014
8.00	IC50	10	nM	CHEMBL150134
8.00	IC50	10	nM	CHEMBL2371036
8.00	Ki	10	nM	CHEMBL4094671
8.00	IC50	10	nM	CHEMBL89668
8.00	Ki	10	nM	CHEMBL420423

PubChem BioAssay actives

680 with measured affinity, of 1200 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
(2R)-N-[(2S)-6-(benzenesulfonamido)-1-oxohexan-2-yl]-2-(methanesulfonamido)-3-phenylmethoxypropanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0020	uM
N-[(2S)-4-(butylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-ethyl-1,1-dioxo-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide	46517: Inhibitory activity tested against human calpain 1 in Molt-4 cells (intact human T-cell leukemia cell line)	ic50	0.0021	uM
(Z)-N-[(2S)-1-[[(2S)-1-[[(2S,3S)-1,3-dihydroxy-5-[[(2S)-1-[[(3S,6S,9E,11R)-3-[(4-hydroxyphenyl)methyl]-4-methyl-2,5,8-trioxo-6-propan-2-yl-1-oxa-4,7-diazacyclododec-9-en-11-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]dec-3-enamide	1469774: Inhibition of human calpain 1 protease using Ac-LLY-AFC as substrate after 1 hr by fluorescence assay	ic50	0.0030	uM
(2R)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]-3-phenylmethoxypropanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0040	uM
(2S)-4-methyl-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]pentanoic acid	262308: Inhibition of isolated human calpain1	ic50	0.0049	uM
6-chloro-2-ethyl-1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3,4-dihydro-1lambda6,2-benzothiazine-3-carboxamide	46509: In vitro inhibitory activity against human calpain I; Not determined	ic50	0.0050	uM
6-chloro-2-methyl-1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3,4-dihydro-1lambda6,2-benzothiazine-3-carboxamide	46353: Inhibitory activity towards human calpain I	ic50	0.0050	uM
2-methyl-1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-7,8-dihydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide	46353: Inhibitory activity towards human calpain I	ic50	0.0060	uM
N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-[(E)-2-naphthalen-2-ylethenyl]benzamide	141771: Inhibition of calpain, using human mu-calpain isolated from erythrocytes and Suc-Leu-Tyr-AMC as the fluorogenic substrate	ki	0.0060	uM
(2S)-3-benzylsulfanyl-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]propanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0060	uM
benzyl N-[(2S)-1-[[(2S)-3,4-dioxo-1-phenyl-4-(phenylmethoxyamino)butan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate	46357: Inhibition of human recombinant Calpain 1	ic50	0.0060	uM
1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3,4-dihydro-2H-1lambda6,2-benzothiazine-3-carboxamide	46510: In vitro inhibitory activity against recombinant human calpain 1	ic50	0.0070	uM
6,7-dichloro-2-methyl-1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3,4-dihydro-1lambda6,2-benzothiazine-3-carboxamide	46353: Inhibitory activity towards human calpain I	ic50	0.0070	uM
(2R)-4-methyl-2-[[4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]pentanoic acid	46724: inhibitory activity measured against recombinant human Calpain-I receptor	ic50	0.0070	uM
benzyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxohexan-2-yl]amino]pentan-2-yl]carbamate	220484: The binding affinity against calpain.	ki	0.0070	uM
2-ethyl-1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide	46353: Inhibitory activity towards human calpain I	ic50	0.0070	uM
(2S)-2-[(4-fluorophenyl)sulfonylamino]-3-methyl-N-[(2R)-4-methyl-1-oxopentan-2-yl]butanamide	141774: In vitro inhibition of porcine mu-calpain.	ic50	0.0075	uM
2,6-dichloro-N-[(2S)-4-[2-[[5-(3-cyanophenyl)thiophen-2-yl]sulfonylamino]ethylamino]-3,4-dioxo-1-phenylbutan-2-yl]benzamide	46718: Inhibitory activity against recombinant human calpain I	ki	0.0080	uM
2-ethyl-1,1-dioxo-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-7,8-dihydro-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide	46353: Inhibitory activity towards human calpain I	ic50	0.0080	uM
(2S)-N-[(3S)-2-hydroxyoxolan-3-yl]-4-methyl-2-[[2-[[2-(10H-phenothiazin-2-yloxy)acetyl]amino]acetyl]amino]pentanamide	262308: Inhibition of isolated human calpain1	ic50	0.0080	uM
N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-2-(4H-chromeno[4,3-c]pyrazol-2-yl)pyridine-3-carboxamide	1458567: Inhibition of human erythrocytes calpain-1 using Suc-Leu-Tyr-AMC as substrate by kinetic fluorescence assay	ki	0.0080	uM
benzyl N-[(2S)-3-methyl-1-oxo-1-[[(2S)-1-oxo-3-phenylpropan-2-yl]amino]butan-2-yl]carbamate	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0080	uM
(2R)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-phenylmethoxypropanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0080	uM
N-(1-amino-1-oxo-3-phenylpropan-2-yl)-2-[(E)-2-naphthalen-1-ylethenyl]benzamide	46526: Inhibitory activity against human Calpain 1 isolated from erythrocytes	ki	0.0084	uM
3-[[4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-2-oxo-4-phenylbutanoic acid	46528: Inhibitory activity of alpha-keto esters towards calpain 1 at pH 8.0.	ki	0.0085	uM
N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-1-(1-benzothiophene-2-carbonyl)piperidine-4-carboxamide	141772: Inhibition of Suc-Leu-Tyr-AMC binding to human mu-calpain from erythrocytes	ki	0.0090	uM
(2R)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-phenylmethoxy-2-(thiophen-2-ylsulfonylamino)propanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0090	uM
(2R)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-2-phenylacetamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0090	uM
(2R)-2-(ethylsulfonylamino)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-phenylmethoxypropanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0090	uM
N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-1-(1-benzothiophen-2-yl)piperidine-4-carboxamide	1500341: Inhibition of human erythrocytes mu-calpain using SucLeu-Tyr-AMC as substrate	ki	0.0090	uM
(2R)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-phenylmethoxybutanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0090	uM
(2R)-3-(1H-indol-3-yl)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]propanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0100	uM
benzyl N-[(2S)-3-methyl-1-oxo-1-[(1-oxo-3-phenylpropan-2-yl)amino]butan-2-yl]carbamate	46345: Tested for inhibitory activity against calpain.	ki	0.0100	uM
(3S)-3-[[(2R)-2-(methanesulfonamido)-3-phenylmethoxypropanoyl]amino]-2-oxo-4-phenyl-N-[2-[(5-pyridin-2-ylthiophen-2-yl)sulfonylamino]ethyl]butanamide	46730: Inhibitory activity against recombinant human calpain I	ki	0.0100	uM
(2S)-3-methyl-N-[(2R)-4-methyl-1-oxopentan-2-yl]-2-(naphthalen-2-ylsulfonylamino)butanamide	141774: In vitro inhibition of porcine mu-calpain.	ic50	0.0100	uM
N-[(2S)-4-amino-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenylpyrazol-1-yl)pyridine-3-carboxamide	1458567: Inhibition of human erythrocytes calpain-1 using Suc-Leu-Tyr-AMC as substrate by kinetic fluorescence assay	ki	0.0100	uM
benzyl N-[(2S)-1-[[(2S)-4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate	46357: Inhibition of human recombinant Calpain 1	ic50	0.0100	uM
(2S)-3-benzylsulfonyl-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]propanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0110	uM
(2R)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-phenylpropanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0110	uM
(2R)-2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-thiophen-2-ylpropanamide	46727: Inhibitory activity against recombinant human Calpain-I receptor	ki	0.0110	uM
2-(methanesulfonamido)-N-[(2S)-1-oxo-3-phenylpropan-2-yl]-3-phenylmethoxypropanamide	46512: Inhibitory activity against calpain-I	ic50	0.0110	uM
(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-phenylpropanoic acid	46510: In vitro inhibitory activity against recombinant human calpain 1	ic50	0.0110	uM
benzyl N-[(2R)-1-[[(2S)-3,4-dioxo-1-phenyl-4-(phenylmethoxyamino)butan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate	46357: Inhibition of human recombinant Calpain 1	ic50	0.0120	uM
[(3R,5S)-1-(benzenesulfonyl)-5-[[(2S)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-3-yl] benzenesulfonate	46505: Compound was tested for inhibitory activity against recombinant human Calpain 1	ic50	0.0130	uM
(2S)-2-[(4-chlorophenyl)sulfonylamino]-N-[(2R)-1-(1H-indol-3-yl)-3-oxopropan-2-yl]-3-methylbutanamide	141774: In vitro inhibition of porcine mu-calpain.	ic50	0.0130	uM
N-(1-amino-1-oxohexan-2-yl)-2-[(E)-2-[4-[(dimethylamino)methyl]phenyl]ethenyl]benzamide	46526: Inhibitory activity against human Calpain 1 isolated from erythrocytes	ki	0.0133	uM
N-[(2S)-3,4-dioxo-1-phenyl-4-[2-[(5-pyridin-2-ylthiophen-2-yl)sulfonylamino]ethylamino]butan-2-yl]-2,6-difluorobenzamide	46718: Inhibitory activity against recombinant human calpain I	ki	0.0140	uM
(2R)-1-(4-methylphenyl)sulfonyl-N-[(2S)-1-oxo-3-phenylpropan-2-yl]pyrrolidine-2-carboxamide	46505: Compound was tested for inhibitory activity against recombinant human Calpain 1	ic50	0.0140	uM
N-[(2S)-4-[2-[[5-[3-(acetamidomethyl)phenyl]thiophen-2-yl]sulfonylamino]ethylamino]-3,4-dioxo-1-phenylbutan-2-yl]-2,6-dichlorobenzamide	46718: Inhibitory activity against recombinant human calpain I	ki	0.0140	uM
(2S)-2-[(4-chlorophenyl)sulfonylamino]-3-methyl-N-[(2R)-1-oxo-3-phenylpropan-2-yl]butanamide	141774: In vitro inhibition of porcine mu-calpain.	ic50	0.0140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases cleavage, increases expression, decreases reaction	5
Particulate Matter	decreases expression, increases abundance, increases expression	4
bisphenol A	decreases expression, increases expression, increases methylation	3
sodium arsenite	increases abundance, increases cleavage, increases degradation, increases reaction, increases expression	3
Calcium	affects cotreatment, increases activity, increases reaction, increases degradation, increases cleavage (+1 more)	3
Cisplatin	increases response to substance, affects reaction, increases cleavage, decreases expression, decreases reaction (+3 more)	3
calpeptin	decreases reaction, increases degradation, increases activity	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Arsenic	increases abundance, increases cleavage, increases degradation, increases reaction, increases expression	2
Paraquat	decreases reaction, increases activity, increases expression	2
Sodium Chloride	decreases reaction, affects cotreatment, affects localization, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Simvastatin	increases expression	2
bisphenol F	affects cotreatment, affects expression	1
lasiocarpine	increases expression, increases metabolic processing	1
surfactin peptide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decamethrin	affects response to substance	1
fisetin	decreases reaction, increases expression	1
tanshinone	decreases reaction, increases expression	1
1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid	decreases reaction, increases expression	1
coumarin	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation	1
casticin	increases cleavage, increases expression	1
MDL 201053	decreases expression, decreases reaction, increases degradation	1
glimepiride	increases expression	1
calpain inhibitor III	decreases reaction, increases response to substance, decreases activity	1

ChEMBL screening assays

213 unique, capped per target: 202 binding, 10 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL653673	Binding	Inhibition of Calpain 1 by [3H]acetyl-casein assay	Characterization of a continuous fluorogenic assay for calpain I. Kinetic evaluation of peptide aldehydes, halomethyl ketones and (acyloxy)methyl ketones as inhibitors of the enzyme — Bioorg Med Chem Lett
CHEMBL5627052	Toxicity	Inhibition of human calpain 1 at 100 uM relative to control	Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease. — Eur J Med Chem
CHEMBL5723079	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002134a CAPN1	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D1VH	Abcam A-549 CAPN1 KO	Cancer cell line	Male
CVCL_D2A3	Abcam HCT 116 CAPN1 KO	Cancer cell line	Male
CVCL_D9AY	Ubigene HEK293 CAPN1 KO	Transformed cell line	Female
CVCL_SG77	HAP1 CAPN1 (-)	Cancer cell line	Male
CVCL_UL68	FJMUi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia