CAPN9

Summary

CAPN9 (calpain 9, HGNC:1486) is a protein-coding gene on chromosome 1q42.2, encoding Calpain-9 (O14815). Calcium-regulated non-lysosomal thiol-protease.

Calpains are ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large subunit possesses a cysteine protease domain, and both subunits possess calcium-binding domains. Calpains have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. The protein encoded by this gene is expressed predominantly in stomach and small intestine and may have specialized functions in the digestive tract. This gene is thought to be associated with gastric cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10753 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 130 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_006615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1486
Approved symbol	CAPN9
Name	calpain 9
Location	1q42.2
Locus type	gene with protein product
Status	Approved
Aliases	nCL-4, GC36
Ensembl gene	ENSG00000135773
Ensembl biotype	protein_coding
OMIM	606401
Entrez	10753

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000271971, ENST00000354537, ENST00000366666, ENST00000480004, ENST00000907306, ENST00000907307, ENST00000907308, ENST00000940880

RefSeq mRNA: 3 — MANE Select: NM_006615 NM_001319676, NM_006615, NM_016452

CCDS: CCDS1586, CCDS31053, CCDS81431

Canonical transcript exons

ENST00000271971 — 20 exons

Exon	Start	End
ENSE00000921431	230755337	230755406
ENSE00000961374	230759512	230759630
ENSE00000961375	230762653	230762786
ENSE00000961376	230767541	230767709
ENSE00000961377	230769180	230769263
ENSE00000961378	230772014	230772099
ENSE00000961379	230774554	230774631
ENSE00000961380	230778973	230779133
ENSE00000961381	230780179	230780336
ENSE00000961382	230780500	230780708
ENSE00000961383	230785981	230786017
ENSE00000961384	230787522	230787602
ENSE00000961385	230790132	230790189
ENSE00000961386	230791864	230791928
ENSE00001416134	230798162	230798220
ENSE00003458284	230795163	230795279
ENSE00003488414	230792850	230792928
ENSE00003581219	230792426	230792494
ENSE00003843552	230801570	230801989
ENSE00003849940	230747388	230747709

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 86.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0657 / max 68.3503, expressed in 127 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9037	0.8885	123
9038	0.1772	102

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	86.39	gold quality
rectum	UBERON:0001052	85.44	gold quality
mucosa of transverse colon	UBERON:0004991	82.06	gold quality
spinal cord	UBERON:0002240	81.72	gold quality
body of stomach	UBERON:0001161	81.54	gold quality
mucosa of stomach	UBERON:0001199	81.35	gold quality
ileal mucosa	UBERON:0000331	80.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.88	gold quality
stomach	UBERON:0000945	78.53	gold quality
bronchial epithelial cell	CL:0002328	78.42	gold quality
transverse colon	UBERON:0001157	77.89	gold quality
pancreatic ductal cell	CL:0002079	76.62	silver quality
right lung	UBERON:0002167	76.21	gold quality
mucosa of sigmoid colon	UBERON:0004993	75.75	gold quality
colonic mucosa	UBERON:0000317	75.19	gold quality
epithelium of bronchus	UBERON:0002031	75.05	gold quality
minor salivary gland	UBERON:0001830	74.86	gold quality
endometrium epithelium	UBERON:0004811	74.49	silver quality
bronchus	UBERON:0002185	74.24	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.71	gold quality
amygdala	UBERON:0001876	72.52	gold quality
small intestine	UBERON:0002108	71.52	gold quality
mouth mucosa	UBERON:0003729	70.35	gold quality
upper lobe of left lung	UBERON:0008952	70.02	gold quality
putamen	UBERON:0001874	69.01	gold quality
intestine	UBERON:0000160	69.00	gold quality
fundus of stomach	UBERON:0001160	68.89	gold quality
saliva-secreting gland	UBERON:0001044	68.87	gold quality
upper lobe of lung	UBERON:0008948	68.61	gold quality
hypothalamus	UBERON:0001898	68.46	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting CAPN9, 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-4786-3P	99.36	68.35	1390
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-218-1-3P	98.63	67.97	832
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-148B-5P	97.29	66.30	992
HSA-MIR-6874-3P	97.29	66.34	975
HSA-MIR-585-3P	91.80	66.07	57

Literature-anchored findings (GeneRIF, showing 4)

• 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)
• calpain-9 may play a role in breast cancer and that low expression is associated with poorer patient clinical outcome following endocrine therapy. (PMID:25539577)
• Study shows that calpain-9 is a tumor suppressor that can be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer. (PMID:27404891)
• these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism. (PMID:31316008)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	capn9	ENSDARG00000012341
mus_musculus	Capn9	ENSMUSG00000031981
rattus_norvegicus	Capn9	ENSRNOG00000018480
drosophila_melanogaster	CalpA	FBGN0012051
caenorhabditis_elegans		WBGENE00000542
caenorhabditis_elegans	clp-3	WBGENE00000544
caenorhabditis_elegans		WBGENE00000546
caenorhabditis_elegans		WBGENE00000547
caenorhabditis_elegans	clp-8	WBGENE00009695
caenorhabditis_elegans	clpr-3	WBGENE00010417
caenorhabditis_elegans	clpr-1	WBGENE00012233
caenorhabditis_elegans	clpr-3	WBGENE00013184

Paralogs (20): CAPN1 (ENSG00000014216), SRI (ENSG00000075142), CAPN6 (ENSG00000077274), CAPN3 (ENSG00000092529), CAPN15 (ENSG00000103326), GCA (ENSG00000115271), ADGB (ENSG00000118492), CAPNS1 (ENSG00000126247), CAPN7 (ENSG00000131375), 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-9 — O14815 (reviewed: O14815)

Alternative names: Digestive tract-specific calpain, New calpain 4, Protein CG36

All UniProt accessions (2): E7ESS6, O14815

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-regulated non-lysosomal thiol-protease.

Tissue specificity. Expressed predominantly in stomach.

Induction. Down-regulated in gastric cancer tissue and in gastric cell lines of differentiated and poorly differentiated types.

Similarity. Belongs to the peptidase C2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O14815-1	1	yes
O14815-2	2, CG36

RefSeq proteins (3): NP_001306605, NP_006606, NP_057536 (=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.B28 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)
• EC 3.4.22.B29 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (75 total): binding site 19, strand 16, helix 15, sequence variant 12, domain 4, region of interest 4, active site 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1ZIV	X-RAY DIFFRACTION	2.31
2P0R	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14815-F1	90.14	0.69

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 (3): 254; 278; 97

Ligand- & substrate-binding residues (19): 81; 83; 88; 167; 284; 291; 312; 314; 316; 574; 576; 578 …

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 62 (showing top): GOBP_DIGESTION, GOZGIT_ESR1_TARGETS_DN, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GGARNTKYCCA_UNKNOWN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, ABBUD_LIF_SIGNALING_1_DN, SANSOM_APC_TARGETS_DN, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_DN, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_CALCIUM_DEPENDENT_CYSTEINE_TYPE_ENDOPEPTIDASE_ACTIVITY, MARTENS_TRETINOIN_RESPONSE_UP, VECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_DN

GO Biological Process (2): proteolysis (GO:0006508), digestion (GO:0007586)

GO Molecular Function (6): calcium-dependent cysteine-type endopeptidase activity (GO:0004198), calcium ion binding (GO:0005509), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (1): cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
multicellular organismal process	1
cysteine-type endopeptidase activity	1
metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1047 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAPN9	GKN1	Q9NS71	941
CAPN9	CAST	P20810	591
CAPN9	CWH43	Q9H720	501
CAPN9	SUSD1	Q6UWL2	500
CAPN9	CACNG1	Q06432	459
CAPN9	CYP2F1	P24903	455
CAPN9	CCKBR	P32239	454
CAPN9	ACSM1	Q08AH1	453
CAPN9	GALNT3	Q14435	451
CAPN9	TOM1L1	O75674	444
CAPN9	PDLIM3	Q53GG5	444
CAPN9	RASD2	Q96D21	441
CAPN9	CAPN8	A6NHC0	439
CAPN9	SLC2A12	Q8TD20	436
CAPN9	TANC2	Q9HCD6	425

IntAct

0 interactions, top by confidence:

BioGRID (8): CAPN9 (Co-fractionation), MPI (Co-fractionation), CAPN9 (Affinity Capture-MS), CAPN9 (Negative Genetic), CAPN9 (Negative Genetic), CAPN9 (Negative Genetic), CAPN9 (Negative Genetic), PRPF8 (Cross-Linking-MS (XL-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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	100
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2425124	NC_000001.10:g.(?230203028)(231413288_?)del	Pathogenic

SpliceAI

2776 predictions. Top by Δscore:

Variant	Effect	Δscore
1:230762643:T:TA	acceptor_gain	1.0000
1:230762644:G:A	acceptor_gain	1.0000
1:230762648:A:AG	acceptor_gain	1.0000
1:230762650:CAGTT:C	acceptor_loss	1.0000
1:230762651:A:AG	acceptor_gain	1.0000
1:230762651:A:C	acceptor_loss	1.0000
1:230762652:G:GA	acceptor_gain	1.0000
1:230762652:GT:G	acceptor_gain	1.0000
1:230762652:GTT:G	acceptor_gain	1.0000
1:230762652:GTTC:G	acceptor_gain	1.0000
1:230762652:GTTCT:G	acceptor_gain	1.0000
1:230762782:GCCAA:G	donor_gain	1.0000
1:230762784:CAAGT:C	donor_loss	1.0000
1:230762785:AAGT:A	donor_loss	1.0000
1:230762786:AGT:A	donor_loss	1.0000
1:230762787:G:GG	donor_gain	1.0000
1:230762787:G:T	donor_loss	1.0000
1:230762788:TGAG:T	donor_loss	1.0000
1:230762789:GAGT:G	donor_loss	1.0000
1:230767531:A:AG	acceptor_gain	1.0000
1:230767532:C:G	acceptor_gain	1.0000
1:230767536:T:A	acceptor_gain	1.0000
1:230767536:TGCA:T	acceptor_loss	1.0000
1:230767539:A:AC	acceptor_loss	1.0000
1:230767539:A:AG	acceptor_gain	1.0000
1:230767539:AG:A	acceptor_gain	1.0000
1:230767540:G:GG	acceptor_gain	1.0000
1:230767540:GG:G	acceptor_gain	1.0000
1:230767540:GGC:G	acceptor_gain	1.0000
1:230767540:GGCT:G	acceptor_gain	1.0000

AlphaMissense

4607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:230747695:T:A	W67R	0.998
1:230747695:T:C	W67R	0.998
1:230779091:T:A	W358R	0.998
1:230779091:T:C	W358R	0.998
1:230762690:A:T	D147V	0.997
1:230762755:T:A	W169R	0.997
1:230762755:T:C	W169R	0.997
1:230779113:G:A	G365E	0.997
1:230759613:G:T	G129W	0.996
1:230774627:T:C	F317L	0.996
1:230774629:C:A	F317L	0.996
1:230774629:C:G	F317L	0.996
1:230779093:G:C	W358C	0.996
1:230779093:G:T	W358C	0.996
1:230779110:C:A	A364D	0.996
1:230779112:G:T	G365W	0.996
1:230780195:T:A	N377K	0.996
1:230780195:T:G	N377K	0.996
1:230780638:A:C	S471R	0.996
1:230780640:C:A	S471R	0.996
1:230780640:C:G	S471R	0.996
1:230780668:T:C	F481L	0.996
1:230780670:C:A	F481L	0.996
1:230780670:C:G	F481L	0.996
1:230759614:G:A	G129E	0.995
1:230762689:G:C	D147H	0.995
1:230762696:G:C	R149P	0.995
1:230762774:A:T	K175I	0.995
1:230762783:C:A	A178D	0.995
1:230772054:G:C	R277P	0.995

dbSNP variants (sampled 300 via entrez): RS1000038725 (1:230788722 C>G), RS1000042529 (1:230752709 C>T), RS1000089052 (1:230798381 C>G), RS1000121841 (1:230797917 G>A), RS1000152877 (1:230788501 C>T), RS1000154843 (1:230750276 A>G), RS1000237412 (1:230767340 G>A), RS1000309943 (1:230800201 G>C,T), RS1000342086 (1:230770106 C>A,T), RS1000415715 (1:230769932 A>G,T), RS1000487457 (1:230749035 C>A,T), RS1000573101 (1:230766065 A>G), RS1000643151 (1:230754328 C>A,T), RS1000774689 (1:230749329 A>G), RS1000817697 (1:230787875 A>G)

Disease associations

OMIM: gene MIM:606401 | disease phenotypes: MIM:617395

GenCC curated gene-disease

Mondo (1): congenital disorder of glycosylation, type IIq (MONDO:0054559)

Orphanet (1): COG2-CDG (Orphanet:435934)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001712_1	Myopia (pathological)	7.000000e-06
GCST005173_63	Coronary artery calcified atherosclerotic plaque (130 HU threshold) in type 2 diabetes	7.000000e-06
GCST008359_10	Response to cognitive-behavioural therapy in anxiety disorder	8.000000e-06
GCST008367_5	Plasma anti-thyroglobulin and anti-thyroid peroxidase levels (bivariate analysis)	1.000000e-06
GCST010866_29	Coronary artery disease	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0004723	coronary artery calcification
EFO:0007820	cognitive behavioural therapy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523126 (SINGLE PROTEIN)

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 15 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.79	IC50	1610	nM	CHEMBL423112
5.65	IC50	2230	nM	CHEMBL288365
5.63	IC50	2350	nM	CHEMBL356841
5.55	IC50	2840	nM	CALPEPTIN
5.48	IC50	3320	nM	CHEMBL318779
5.20	IC50	6250	nM	CHEMBL406405
5.17	IC50	6680	nM	CHEMBL1892491
5.03	IC50	9240	nM	CHEMBL4440290
5.00	IC50	9880	nM	MG-132

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
o,p’-DDT	increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
entinostat	decreases expression	1
Resveratrol	increases expression	1
Benzo(a)pyrene	affects methylation	1
Diethylnitrosamine	decreases expression	1
Diethylstilbestrol	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Menthol	decreases expression	1
Methapyrilene	increases methylation	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Thimerosal	increases expression	1
Urethane	decreases expression	1
Zearalenone	increases expression	1
Zinc	affects cotreatment, affects expression	1
Genistein	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4420659	Binding	Inhibition of human recombinant mini-CAPN9 pre-incubated for 10 mins before calpain FRET peptide 5-FAM /QXL520 substrate addition by FLIPR assay	Targeting capn9/capns2 activity as a therapeutic strategy for the treatment of myofibroblast differentiation and associated pathologies

Clinical trials (associated diseases)

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