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): 406 total — 35 pathogenic, 10 likely-pathogenic (top 8% of genes corpus-wide)
• GTEx eGene: eQTL in 24 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 34
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.98 (unconstrained)
• MANE Select transcript: NM_005186
• Interaction hub: 1,850 STRING partners (top 9% of genes corpus-wide)

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: 35 — 20 protein_coding, 8 retained_intron, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

MANE Select: ENST00000279247

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 4, TSL 3: 8, TSL 4: 7, TSL 5: 5

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, ENST00001002866, ENST00001030905, ENST00001030906, ENST00001063033, ENST00001063034, ENST00001142711

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.

Highest expression (Bgee): lower esophagus mucosa, endometrium epithelium, esophagus mucosa, mucosa of transverse colon, skin of abdomen.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CAPN1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 26 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	6.4e-41	+0.19	11:65176711:A:G
Artery Tibial	eqtl	4.9e-24	+0.30	11:65132799:G:T
Adipose Subcutaneous	eqtl	1.1e-12	+0.16	11:65174945:G:T
Stomach	eqtl	1.2e-08	+0.15	11:65179769:T:C
Colon Transverse	eqtl	1.1e-07	+0.11	11:65176711:A:G
Nerve Tibial	eqtl	4.3e-07	+0.15	11:65180806:A:C
Skin Sun Exposed Lower leg	eqtl	6.3e-06	+0.26	11:65187332:G:A
Muscle Skeletal	eqtl	3.3e-05	-0.21	11:65148306:A:C
Cells Cultured fibroblasts	eqtl	1.0e-04	-0.10	11:65183956:G:C
Stomach	sqtl	2.0e-04	-2.06	11:65507983:G:C
Uterus	eqtl	2.0e-04	-1.56	11:65614773:G:A
Brain Cerebellum	eqtl	4.2e-04	+0.89	11:65183001:A:G
Thyroid	eqtl	5.2e-04	+0.08	11:65176711:A:G
Brain Spinal cord cervical c-1	eqtl	6.5e-04	+1.17	11:65004596:G:T
Esophagus Mucosa	eqtl	9.3e-04	+0.07	11:65183956:G:C
Lung	eqtl	1.1e-03	+0.10	11:65180806:A:C
Adipose Visceral Omentum	eqtl	1.9e-03	+0.10	11:65174945:G:T
Artery Aorta	eqtl	6.1e-03	+0.15	11:65184439:ACT:A
Pancreas	eqtl	6.8e-03	+0.12	11:65181084:A:G
Breast Mammary Tissue	eqtl	9.8e-03	+0.09	11:65180806:A:C

FANTOM5 promoters

showing 10 of 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

showing 100 of 283 tissues 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
saliva-secreting gland	UBERON:0001044	96.51	gold quality
monocyte	CL:0000576	96.48	gold quality
apex of heart	UBERON:0002098	96.48	gold quality
left uterine tube	UBERON:0001303	96.46	gold quality
right lung	UBERON:0002167	96.45	gold quality
adenohypophysis	UBERON:0002196	96.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.20	gold quality
body of uterus	UBERON:0009853	96.18	gold quality
upper lobe of lung	UBERON:0008948	96.02	gold quality
nerve	UBERON:0001021	96.01	gold quality
tibial nerve	UBERON:0001323	96.01	gold quality
right coronary artery	UBERON:0001625	96.00	gold quality
right ovary	UBERON:0002118	95.98	gold quality
stromal cell of endometrium	CL:0002255	95.95	gold quality
leukocyte	CL:0000738	95.94	gold quality
mononuclear cell	CL:0000842	95.88	gold quality
stomach	UBERON:0000945	95.87	gold quality
small intestine	UBERON:0002108	95.84	gold quality
zone of skin	UBERON:0000014	95.78	gold quality
cerebellar hemisphere	UBERON:0002245	95.71	gold quality
left coronary artery	UBERON:0001626	95.67	gold quality
cerebellar cortex	UBERON:0002129	95.63	gold quality
ascending aorta	UBERON:0001496	95.62	gold quality
thoracic aorta	UBERON:0001515	95.61	gold quality
popliteal artery	UBERON:0002250	95.59	gold quality
tibial artery	UBERON:0007610	95.58	gold quality
rectum	UBERON:0001052	95.56	gold quality
aorta	UBERON:0000947	95.52	gold quality
descending thoracic aorta	UBERON:0002345	95.50	gold quality
right adrenal gland	UBERON:0001233	95.44	gold quality
right atrium auricular region	UBERON:0006631	95.44	gold quality
left ovary	UBERON:0002119	95.43	gold quality
right adrenal gland cortex	UBERON:0035827	95.37	gold quality
right lobe of liver	UBERON:0001114	95.35	gold quality
left adrenal gland cortex	UBERON:0035825	95.23	gold quality
right frontal lobe	UBERON:0002810	95.17	gold quality
left adrenal gland	UBERON:0001234	95.11	gold quality
gastrocnemius	UBERON:0001388	95.07	gold quality
spleen	UBERON:0002106	95.05	gold quality
coronary artery	UBERON:0001621	94.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.89	gold quality
pituitary gland	UBERON:0000007	94.82	gold quality
colon	UBERON:0001155	94.68	gold quality
tonsil	UBERON:0002372	94.63	gold quality
pancreas	UBERON:0001264	94.59	gold quality
muscle of leg	UBERON:0001383	94.48	gold quality
paraflocculus	UBERON:0005351	94.36	gold quality
intestine	UBERON:0000160	94.35	gold quality
omental fat pad	UBERON:0010414	94.34	gold quality
peritoneum	UBERON:0002358	94.29	gold quality
adrenal cortex	UBERON:0001235	94.22	gold quality
cardiac atrium	UBERON:0002081	94.18	gold quality
large intestine	UBERON:0000059	94.11	gold quality
islet of Langerhans	UBERON:0000006	93.99	gold quality
fundus of stomach	UBERON:0001160	93.94	gold quality
cerebellum	UBERON:0002037	93.93	gold quality
heart left ventricle	UBERON:0002084	93.86	gold quality
lymph node	UBERON:0000029	93.85	gold quality
cingulate cortex	UBERON:0003027	93.69	gold quality
anterior cingulate cortex	UBERON:0009835	93.69	gold quality
sigmoid colon	UBERON:0001159	93.65	gold quality
prostate gland	UBERON:0002367	93.65	gold quality
adrenal gland	UBERON:0002369	93.60	gold quality
colonic epithelium	UBERON:0000397	93.46	gold quality
cardiac ventricle	UBERON:0002082	93.38	gold quality
uterine cervix	UBERON:0000002	93.22	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.22	gold quality
smooth muscle tissue	UBERON:0001135	93.12	gold quality
heart	UBERON:0000948	92.93	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Esophagus	tissue	216.1	high
Skin 1	tissue	118.3	medium
Vagina	tissue	112.9	high
Salivary gland	tissue	88.4	high
Fallopian tube	tissue	86.8	high
Small intestine	tissue	83.0	high
Tonsil	tissue	80.9	high
Skeletal muscle	tissue	79.5	low
Urinary bladder	tissue	78.1	high
Duodenum	tissue	75.6	high
Locus coeruleus	tissue	75.4
Colon	tissue	73.7	high
Cervix	tissue	68.2	high
Pancreas	tissue	67.6	high
Thyroid gland	tissue	64.2	high
Seminal vesicle	tissue	63.6	high
Bone marrow	tissue	62.8	high
Choroid plexus	tissue	62.5
Postcentral gyrus	tissue	61.5
Stomach 1	tissue	60.6	high
Spinal cord	tissue	59.3
Hippocampus	tissue	56.3	medium
Rectum	tissue	54.1	high
Lung	tissue	53.5	medium
Lymph node	tissue	53.3	high
Placenta	tissue	52.8	high
Gallbladder	tissue	52.1	high
Tongue	tissue	51.5
Heart muscle	tissue	49.7	low
Appendix	tissue	48.9	high
Prostate	tissue	47.7	high
Nucleus accumbens	tissue	46.3
Thymus	tissue	46.0
Superior colliculi	tissue	44.7
Smooth muscle	tissue	42.3	low
Pons	tissue	40.7
Spleen	tissue	39.5	high
Pituitary gland	tissue	38.7
Adipose tissue	tissue	37.1	not detected
Ovary	tissue	36.8	high
Medulla oblongata	tissue	36.5
Thalamus	tissue	36.2
Parathyroid gland	tissue	34.4	medium
Endometrium 1	tissue	33.0	high
Cerebral cortex	tissue	32.8	high
Somatosensory cortex	tissue	32.8
Substantia nigra	tissue	32.6
Hippocampal formation	tissue	32.3
Motor cortex	tissue	32.1
Occipital cortex	tissue	31.8
Prefrontal cortex	tissue	31.3
Breast	tissue	30.7	high
Midbrain	tissue	30.6
Cerebellum	tissue	30.6	medium
Hypothalamus	tissue	30.5
Liver	tissue	29.9	high
Kidney	tissue	29.6	high
Retrosplenial cortex	tissue	29.3
Entorhinal cortex	tissue	28.6
Retrosplenial and cingulate cortex	tissue	28.5

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Nuclei of the trapezoid body (93.3), Nucleus raphe magnus (89.3), Pontine nuclei (88.6), Posterior thalamic nucleus (84.8), Spinal trigeminal nucleus, interpolar (83.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

Targeting CAPN1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 41 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 2.84e-20, LOEUF 0.977, missense Z 1.61 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000279247 — one region, missense o/e 0.85.

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	si:dkeyp-50d11.2	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-4	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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88263) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal platelet physiology	2
premature death	1
abnormal blood coagulation	1
increased heart weight	1
abnormal leukocyte adhesion	1
abnormal heart left ventricle morphology	1
decreased heart ventricle muscle contractility	1
decreased physiological sensitivity to xenobiotic	1
abnormal platelet dense granule physiology	1
decreased platelet aggregation	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R4U9	100.0%	Diamond
Macaca fascicularis	Q9GLG1	99.4%	Diamond
Bos taurus	P51186	97.6%	Diamond
Ovis aries	Q9TTH8	97.6%	Diamond
Sus scrofa	P04574	97.4%	Diamond
Cricetulus griseus	P05044	97.0%	Diamond
Oryctolagus cuniculus	P06813	97.0%	Diamond
Oryza sativa Japonica Group	Q6ZFZ4	90.9%	Diamond
Zea mays	Q8RVL1	90.9%	Diamond
Gallus gallus	Q92178	81.3%	Diamond
Arabidopsis thaliana	Q8RVL2	71.0%	Diamond
Drosophila melanogaster	Q11002	68.8%	Diamond
Schistosoma mansoni	P27730	43.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CDC42EP2	protein-coding	10435
POLA2	protein-coding	23649
CAPN1-AS1	ncRNA	728975
SPDYC	protein-coding	387778

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. Ubiquitinated via ‘Lys6’-, ‘Lys27’-, ‘Lys29’-, and ‘Lys63’-linked chains by the E3 ubiquitin ligase complex at least composed of CUL3, KCTD7 and RBX1 to execute atypical, non-degradative ubiquitination.

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 (70 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, cross-link 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
7W7O	The crystal structure of human Calpain-1 protease core in complex with 14a	X-RAY DIFFRACTION	1.59
7X79	The crystal structure of human Calpain-1 protease core in complex with 14b	X-RAY DIFFRACTION	1.8
8GX3	The crystal structure of human Calpain-1 protease core in complex with 14c	X-RAY DIFFRACTION	1.99
1ZCM	Human calpain protease core inhibited by ZLLYCH2F	X-RAY DIFFRACTION	2
2ARY	Catalytic domain of Human Calpain-1	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · IF supported

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)

Position	Role
115
272
296
15–16	cleavage; for 78 kda form
27–28	cleavage; for 75 kda form

Ligand- & substrate-binding residues (15)

Position	Role
109	Ca(2+)
114	Ca(2+)
316	Ca(2+)
318	Ca(2+)
323	Ca(2+)
598	Ca(2+)
600	Ca(2+)
602	Ca(2+)
604	Ca(2+)
609	Ca(2+)
628	Ca(2+)
630	Ca(2+)
632	Ca(2+)
634	Ca(2+)
639	Ca(2+)

Post-translational modifications (3)

Type	Positions
N-acetylserine	2
Phosphothreonine	354
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	398

Mutagenesis-validated functional residues (1)

Position	Phenotype
398	complete loss of ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 13; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

13 pathways:

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

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 (6): proteolysis (GO:0006508), positive regulation of cell population proliferation (GO:0008284), regulation of macroautophagy (GO:0016241), regulation of catalytic activity (GO:0050790), 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 (11): 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), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

9 top-level categories:

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

30 GO namespaces:

Category	Terms
cellular anatomical structure	4
catalytic activity	2
cytoplasm	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
regulation of molecular function	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
intracellular organelle lumen	1
ficolin-1-rich granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
proteolysis	BP	direct assay
regulation of catalytic activity	BP	direct assay
self proteolysis	BP	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
focal adhesion	CC	high-throughput assay
membrane	CC	direct assay
plasma membrane	CC	direct assay
calcium ion binding	MF	direct assay
calcium-dependent cysteine-type endopeptidase activity	MF	direct assay
peptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,850 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAPN1	CAST	P20810	937
CAPN1	AHNAK	Q09666	783
CAPN1	PYGM	P11217	782
CAPN1	MAP3K11	Q16584	762
CAPN1	FKBP2	P26885	762
CAPN1	FTH1	P02794	761
CAPN1	CHRM1	P11229	760
CAPN1	PLCB3	Q01970	760
CAPN1	COX8A	P10176	758
CAPN1	SF1	Q15637	758
CAPN1	SLC3A2	P08195	758
CAPN1	ROM1	Q03395	757
CAPN1	FOSL1	P15407	757
CAPN1	MARK2	Q7KZI7	755
CAPN1	RELA	Q04206	693

IntAct

Human interaction partners of CAPN1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

21 partners by confidence:

Partner	Interaction type	MIscore	Records
CAPNS1	association	0.840	6
PTPN1	enzymatic reaction	0.680	1
CAPNS2	association	0.640	1
CFTR	physical association	0.600	1
APP	physical association	0.560	3
BAD	physical association	0.560	3
CMPK1	physical association	0.560	3
OPTN	physical association	0.560	3
MAP4	physical association	0.560	1
CAPN8	association	0.530	2
FNTB	association	0.530	1
STAT3	physical association	0.510	2
EZR	cleavage reaction	0.440	2
RCAN1	protein cleavage	0.440	1
TIRAP	cleavage reaction	0.440	1
PDIA3	physical association	0.400	1
ANKRD17	association	0.350	1
ATG7	association	0.350	1
F2R	proximity	0.270	1
GRIN2B	proximity	0.270	1
CLEC4G	physical association	0.000	1

BioGRID (261 interactions; top human partners by supporting records): CAPNS1 (Affinity Capture-MS; 5 records), CAST (Affinity Capture-MS; 5 records), CAPNS2 (Affinity Capture-MS; 4 records), CAPN2 (Affinity Capture-MS; 3 records), FNTB (Affinity Capture-MS; 3 records), KCTD7 (Affinity Capture-Western; 3 records), KNG1 (Affinity Capture-MS; 3 records), LGALS3 (Affinity Capture-MS; 3 records), ATXN3 (Biochemical Activity; 2 records), BAG3 (Affinity Capture-MS; 2 records), CAPN8 (Affinity Capture-MS; 2 records), CD109 (Affinity Capture-MS; 2 records), CD99L2 (Affinity Capture-MS; 2 records), CUL3 (Co-fractionation; 2 records), ECHS1 (Two-hybrid; 2 records)

SIGNOR signaling

10 signaling 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

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ CAPN1-HSP90AB1 complex	2	CAPN1, HSP90AB1
Calpain 1	2	CAPN1, CAPNS1

Disease & clinical

Genetic variants

Variant evidence for CAPN1: 406 ClinVar records (45 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	10
Uncertain significance	165
Likely benign	117
Benign	23

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 45 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
802686	NM_005186.4(CAPN1):c.618_619del (p.Gly208fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
817644	NM_005186.4(CAPN1):c.188dup (p.Val64fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
802687	NM_005186.4(CAPN1):c.1176G>A (p.Trp392Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
617483	NM_005186.4(CAPN1):c.338-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
987432	NM_005186.4(CAPN1):c.759+1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
871873	NM_005186.4(CAPN1):c.1534C>T (p.Arg512Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1029241	NM_005186.4(CAPN1):c.929+2T>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
225767	NM_005186.4(CAPN1):c.407del (p.Pro136fs)	Pathogenic	criteria provided, single submitter	2
986744	NM_005186.4(CAPN1):c.254G>A (p.Trp85Ter)	Pathogenic	criteria provided, single submitter	1
986745	NM_005186.4(CAPN1):c.623G>A (p.Gly208Asp)	Pathogenic	criteria provided, single submitter	1
986748	NM_005186.4(CAPN1):c.1165+1G>A	Pathogenic	criteria provided, single submitter	1
986749	NM_005186.4(CAPN1):c.1341G>C (p.Glu447Asp)	Pathogenic	criteria provided, single submitter	1
986750	NM_005186.4(CAPN1):c.1418_1419del (p.Arg473fs)	Pathogenic	criteria provided, single submitter	1
986751	NM_005186.4(CAPN1):c.1697dup (p.Leu566fs)	Pathogenic	criteria provided, single submitter	1
987184	NM_005186.4(CAPN1):c.759+1G>T	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CAPN1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 1,772):

Position(s)	Effect	Δscore	Sites
11:65183473	acceptor_gain	1.0000
11:65183593–65183594	donor_loss	1.0000	3
11:65185915–65185916	acceptor_loss	1.0000	3
11:65186051	donor_loss	1.0000
11:65187213–65187214	acceptor_loss	1.0000	6
11:65187296	donor_gain	1.0000
11:65187299–65187300	donor_loss	1.0000	4
11:65188489–65188490	donor_loss	1.0000	4
11:65188584–65188585	acceptor_loss	1.0000	5
11:65188714	donor_gain	1.0000

AlphaMissense

2,562 missense substitutions predicted likely pathogenic (of 4,696 scored), across 555 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M593	9	0.898	0.997
M336	9	0.895	0.996
M685	9	0.843	0.985
M635	9	0.825	0.996
H272	8	0.999	1.000
D216	8	0.998	0.999
D106	8	0.996	0.998
D598	8	0.996	0.999
D628	8	0.996	0.997
N296	8	0.995	1.000
D114	8	0.993	0.999
F610	8	0.993	1.000
D309	8	0.992	0.997
F334	8	0.991	1.000
D165	8	0.990	0.998
D166	8	0.990	0.998
N394	8	0.989	0.999
N386	8	0.986	0.999
F585	8	0.986	0.999
D58	8	0.983	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.38e-08
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000977

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
autosomal recessive spastic paraplegia type 76	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Adult-onset neurological disorders	green
Hereditary ataxia, adult onset	green
Hereditary neuropathy or pain disorder	green
Hereditary spastic paraplegia	green
Hereditary spastic paraplegia, adult onset	green
Hereditary spastic paraplegia, childhood onset	green

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 phenotypes (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
HP:0009830	Peripheral neuropathy
HP:0011448	Ankle clonus
HP:0011462	Young adult onset
HP:0034353	Appendicular spasticity

GWAS associations

1 associations:

Study	Trait	p-value
GCST008972_108	Urate levels	1e-23

EFO canonical traits (from GWAS)

1 canonical traits:

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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 758 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL63440	ALOXISTATIN	2	758

PharmGKB: 1 entry (CPIC guideline: no)

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)

713 measured of 812 human assays (816 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[(2S)-3-cyclopropyl-1-[[4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]-3-methoxybenzamide	IC50	0.008 nM	US-11242312: Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof
N-[(2S)-1-[[(2S)-4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-3-methoxybenzamide	IC50	0.03 nM	US-11242312: Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof
(1-{1-Benzyl-2-oxo-2-[3-(3,4,4a,8a-tetrahydro-1H-isoquinolin-2-yl)-propylcarbamoyl]-ethylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester	KI	0.22 nM
(3-Methyl-1-{1-[3-(3,4,4a,8a-tetrahydro-1H-isoquinolin-2-yl)-propylaminooxalyl]-propylcarbamoyl}-butyl)-carbamic acid benzyl ester	KI	0.31 nM
(3-Methyl-1-{1-[3-(3,4,4a,8a-tetrahydro-2H-quinolin-1-yl)-propylaminooxalyl]-propylcarbamoyl}-butyl)-carbamic acid benzyl ester	KI	0.37 nM
(1-{1-Benzyl-2-oxo-2-[3-(3,4,4a,8a-tetrahydro-2H-quinolin-1-yl)-propylcarbamoyl]-ethylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester	KI	0.38 nM
2-Ethyl-1,1-dioxo-1,2,3,4,6,7-hexahydro-5,8-dioxa-1lambda*6*-thia-2-aza-anthracene-3-carboxylic acid ((S)-1-benzyl-2-butylcarbamoyl-2-oxo-ethyl)-amide	IC50	2.1 nM
N-[(2S)-1-[[4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-3-methoxybenzamide	IC50	2.2 nM	US-11242312: Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof
CHEMBL4073900	IC50	3 nM
(S)-2-[(S)-2-((S)-2-Acetylamino-4-methyl-pentanoylamino)-4-methyl-pentanoylamino]-hexanoic acid	KI	3.4 nM
[(S)-1-((S)-1-Formyl-3-methyl-butylcarbamoyl)-2,2-dimethyl-propyl]-carbamic acid benzyl ester	IC50	4 nM
[(S)-1-((S)-1-Formyl-2-methyl-propylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester	IC50	4 nM
(S)-2-((S)-2-(benzyloxycarbonyl)-4-methylpentanamido)-4-methylpentanoic acid	IC50	4.9 nM
6-Chloro-2-ethyl-1,1-dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[e][1,2]thiazine-3-carboxylic acid ((S)-1-benzyl-2-oxo-ethyl)-amide	IC50	5 nM
{(S)-1-[(R)-1-((R)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-ethyl}-carbamic acid benzyl ester	IC50	5 nM
2-Methyl-1,1-dioxo-1,2,6,7-tetrahydro-5,8-dioxa-1lambda*6*-thia-2-aza-anthracene-3-carboxylic acid (1-benzyl-2-oxo-ethyl)-amide	IC50	6 nM
N-(1-Benzyl-2-carbamoyl-2-oxo-ethyl)-2-(2-naphthalen-2-yl-vinyl)-benzamide	KI	6 nM
((S)-1-{(R)-1-[(S)-1-((S)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-3-methyl-butylcarbamoyl}-ethyl)-carbamic acid benzyl ester	IC50	6 nM
(R)-2-(2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-4-methyl-pentanoic acid	IC50	7 nM
1,1-Dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[e][1,2]thiazine-3-carboxylic acid [2-oxo-1-((S)-phenylmethyl)-ethyl]-amide	IC50	7 nM
{(S)-1-[(S)-1-(4-Benzyloxy-benzyl)-2-oxo-ethylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester	IC50	7 nM
N-[(2S)-3-cyclopropyl-1-[[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]-3-methoxybenzamide	IC50	7.1 nM	US-11242312: Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof
2-(4-Fluoro-benzenesulfonylamino)-N-(1-formyl-3-methyl-butyl)-3-methyl-butyramide	IC50	7.5 nM
N-((S)-1-Benzyl-2-{2-[5-(3-cyano-phenyl)-thiophene-2-sulfonylamino]-ethylcarbamoyl}-2-oxo-ethyl)-2,6-dichloro-benzamide	KI	8 nM
(S)-2-(2-(2-(10H-phenothiazin-2-yloxy)acetamido)acetamido)-N-((3S)-2-hydroxy-tetrahydrofuran-3-yl)-4-methylpentanamide	IC50	8 nM
CHEMBL4092996	KI	8 nM
[(S)-1-[(R)-1-((R)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid benzyl ester	IC50	8 nM
[(S)-1-((S)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butyl]-carbamic acid 4-nitro-benzyl ester	IC50	8 nM
[(S)-1-((S)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester	IC50	8 nM
3-(2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-2-oxo-4-phenyl-butyric acid	KI	8.5 nM
(R)-N-((S)-1-Benzyl-2-oxo-ethyl)-2-methanesulfonylamino-2-phenyl-acetamide	KI	9 nM
(R)-N-((S)-1-Benzyl-2-oxo-ethyl)-3-benzyloxy-2-(thiophene-2-sulfonylamino)-propionamide	KI	9 nM
1-(Benzo[b]thiophene-2-carbonyl)-piperidine-4-carboxylic acid (1-benzyl-2-carbamoyl-2-oxo-ethyl)-amide	KI	9 nM
CHEMBL4167219	KI	9 nM
(R)-N-((S)-1-Benzyl-2-oxo-ethyl)-3-(1H-indol-3-yl)-2-methanesulfonylamino-propionamide	KI	10 nM
(S)-3-((R)-3-Benzyloxy-2-methanesulfonylamino-propionylamino)-2-oxo-4-phenyl-N-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-butyramide	KI	10 nM
[(S)-1-((S)-1-Benzyl-2-methoxycarbamoyl-2-oxo-ethylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester	IC50	10 nM
N-(1-Formyl-3-methyl-butyl)-3-methyl-2-(naphthalene-2-sulfonylamino)-butyramide	IC50	10 nM
CHEMBL4094671	KI	10 nM
(S)-2-Methanesulfonylamino-4-methyl-pentanoic acid ((S)-1-formyl-3-methyl-butyl)-amide	IC50	10 nM
[(S)-1-(1-Formyl-propylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester	IC50	10 nM
Naphthalene-2-carboxylic acid {(S)-1-[(R)-1-((R)-1-formyl-3-methyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-amide	IC50	10 nM
(R)-N-((S)-1-Benzyl-2-oxo-ethyl)-3-benzyloxy-2-methanesulfonylamino-propionamide	IC50	11 nM
(S)-N-((S)-1-Benzyl-2-oxo-ethyl)-2-methanesulfonylamino-3-phenylmethanesulfonyl-propionamide	KI	11 nM
N-(1-Benzyl-2-oxo-ethyl)-3-benzyloxy-2-methanesulfonylamino-propionamide	IC50	11 nM
{(S)-1-[(R)-1-((R)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester	IC50	11 nM
[(S)-1-((S)-1-Formyl-3-methyl-butylcarbamoyl)-3-methyl-butyl]-carbamic acid 9H-fluoren-9-ylmethyl ester	IC50	11 nM
[(S)-1-((S)-1-Cyclohexylmethyl-2-oxo-ethylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester	IC50	11 nM
[(R)-1-((S)-1-Benzyl-2-benzyloxycarbamoyl-2-oxo-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid benzyl ester	IC50	12 nM
(S)-2-Acetylamino-4-methyl-pentanoic acid [(R)-1-((R)-1-formyl-pentylcarbamoyl)-3-methyl-butyl]-amide	IC50	12 nM

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

684 with measured affinity, of 1207 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 expression, decreases reaction, increases cleavage	5
Particulate Matter	decreases expression, increases abundance, increases expression	4
bisphenol A	decreases expression, increases expression, increases methylation	3
sodium arsenite	increases degradation, increases reaction, increases expression, increases abundance, increases cleavage	3
Calcium	affects cotreatment, increases activity, increases reaction, increases degradation, increases cleavage (+1 more)	3
Cisplatin	increases expression, decreases expression, affects reaction, increases cleavage, decreases reaction (+3 more)	3
calpeptin	increases activity, decreases reaction, increases degradation	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Arsenic	increases degradation, increases reaction, increases expression, increases abundance, increases cleavage	2
Paraquat	decreases reaction, increases activity, increases expression	2
Sodium Chloride	increases expression, decreases expression, decreases reaction, affects cotreatment, affects localization	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	decreases expression, affects cotreatment, affects localization	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	increases response to substance, decreases activity, decreases reaction	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)

Via MONDO — disease-level, not drug-specific.

1 trials:

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CAPN1 across ~30M SureChEMBL compounds — explore on Sugi Predict.