CAPN8

Summary

CAPN8 (calpain 8, HGNC:1485) is a protein-coding gene on chromosome 1q41, encoding Calpain-8 (A6NHC0). Calcium-regulated non-lysosomal thiol-protease.

Predicted to enable calcium-dependent cysteine-type endopeptidase activity and identical protein binding activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within calcium-dependent self proteolysis. Predicted to be located in Golgi apparatus. Predicted to be active in cytoplasm.

Source: NCBI Gene 388743 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 89 total — 1 pathogenic
• MANE Select transcript: NM_001143962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1485
Approved symbol	CAPN8
Name	calpain 8
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	nCL-2
Ensembl gene	ENSG00000203697
Ensembl biotype	protein_coding
OMIM	618777
Entrez	388743

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000366872, ENST00000366873, ENST00000442247, ENST00000465098, ENST00000467384, ENST00000482183, ENST00000482401, ENST00000484873, ENST00000525760, ENST00000871507, ENST00000961029

RefSeq mRNA: 1 — MANE Select: NM_001143962 NM_001143962

CCDS: CCDS73038

Canonical transcript exons

ENST00000366872 — 21 exons

Exon	Start	End
ENSE00001442855	223619293	223619453
ENSE00001442856	223620192	223620266
ENSE00001442862	223654330	223654399
ENSE00001442863	223665410	223665701
ENSE00001442867	223544772	223544850
ENSE00001442868	223545231	223545299
ENSE00001442869	223549318	223549382
ENSE00001627060	223541616	223541859
ENSE00001779007	223550960	223551017
ENSE00003463374	223544067	223544183
ENSE00003475745	223628009	223628142
ENSE00003487207	223625805	223625888
ENSE00003584759	223626989	223627157
ENSE00003610097	223622815	223622900
ENSE00003628630	223543108	223543166
ENSE00003688923	223628662	223628780
ENSE00003721855	223609153	223609364
ENSE00003727846	223553832	223553900
ENSE00003732651	223558131	223558167
ENSE00003751412	223612246	223612257
ENSE00003786723	223615970	223616145

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 98.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5258 / max 156.4348, expressed in 164 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17637	0.9558	147
17636	0.5333	143
17638	0.0368	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.34	gold quality
ileal mucosa	UBERON:0000331	95.45	gold quality
pylorus	UBERON:0001166	95.11	gold quality
mucosa of stomach	UBERON:0001199	95.00	gold quality
pancreatic ductal cell	CL:0002079	94.70	gold quality
rectum	UBERON:0001052	94.67	gold quality
epithelial cell of pancreas	CL:0000083	93.78	gold quality
upper lobe of left lung	UBERON:0008952	91.29	gold quality
upper lobe of lung	UBERON:0008948	90.73	gold quality
body of stomach	UBERON:0001161	90.02	gold quality
gall bladder	UBERON:0002110	88.77	gold quality
stomach	UBERON:0000945	88.68	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.14	gold quality
colonic mucosa	UBERON:0000317	87.92	gold quality
transverse colon	UBERON:0001157	87.49	gold quality
nasal cavity epithelium	UBERON:0005384	86.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.78	gold quality
minor salivary gland	UBERON:0001830	84.45	gold quality
right lung	UBERON:0002167	84.44	gold quality
lung	UBERON:0002048	83.42	gold quality
fundus of stomach	UBERON:0001160	83.34	gold quality
bronchial epithelial cell	CL:0002328	82.32	gold quality
bronchus	UBERON:0002185	81.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.95	gold quality
vermiform appendix	UBERON:0001154	80.70	gold quality
right uterine tube	UBERON:0001302	80.56	gold quality
mouth mucosa	UBERON:0003729	78.79	gold quality
urinary bladder	UBERON:0001255	78.61	gold quality
metanephros cortex	UBERON:0010533	78.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting CAPN8, 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-513B-5P	99.99	69.96	2150
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-6854-5P	96.77	65.96	848
HSA-MIR-6782-5P	96.45	64.42	612

Literature-anchored findings (GeneRIF, showing 2)

• nCL-2/calpain 8 is active without calpain regulatory subunit and oligomerizes through C2-like domains (PMID:17646163)
• 3 novel loci associated with serum alpha-carotene concentrations among a population that consumed a controlled diet. While replication is necessary, the CAPN2/CAPN8 locus provides compelling evidence for an association with serum alpha-carotene concentrations and may suggest a relationship with the development and progression of cancers. (PMID:28002826)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Capn8	ENSMUSG00000038599
rattus_norvegicus	Capn8	ENSRNOG00000003468
drosophila_melanogaster	CalpB	FBGN0025866
drosophila_melanogaster	Pef	FBGN0033529
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): CAPN1 (ENSG00000014216), 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), CAPN14 (ENSG00000214711), PDCD6 (ENSG00000249915), CAPNS2 (ENSG00000256812)

Protein

Protein identifiers

Calpain-8 — A6NHC0 (reviewed: A6NHC0)

Alternative names: New calpain 2, Stomach-specific M-type calpain

All UniProt accessions (6): A3QK36, A6NHC0, B1B154, H0YDN4, H0YEJ4, H0YEQ4

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-regulated non-lysosomal thiol-protease. Involved in membrane trafficking in the gastric surface mucus cells (pit cells) and may involve the membrane trafficking of mucus cells via interactions with coat protein. Proteolytically cleaves the beta-subunit of coatomer complex.

Subunit / interactions. Monomer and homooligomer. Interacts with COPS1/GPS1, COPB1, EYA2, NME2, NME4 and TOMM70.

Subcellular location. Cytoplasm. Golgi apparatus.

Tissue specificity. Stomach.

Post-translational modifications. Undergoes autolytic cleavage between Ala-5 and Ala-6 which gives rise to fragments extending from Ala-6 to the C-terminus, Ala-6 to the EF-hand 2 domain and from Ala-6 to the beginning of domain III.

Cofactor. Binds 2 calcium ions.

Domain organisation. The domain III mediates oligomerization.

Similarity. Belongs to the peptidase C2 family.

RefSeq proteins (1): NP_001137434* (*=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

Enzyme classification (BRENDA):

• EC 3.4.22.B28 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (50 total): helix 15, strand 13, binding site 10, domain 4, active site 3, sequence conflict 2, chain 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2NQA	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NHC0-F1	89.15	0.60

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): 105; 262; 286

Ligand- & substrate-binding residues (10): 590; 592; 594; 599; 618; 620; 622; 624; 629; 588

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: 60 (showing top): GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, GOMF_CALCIUM_DEPENDENT_CYSTEINE_TYPE_ENDOPEPTIDASE_ACTIVITY, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_WITH_LMP1_UP, STAMBOLSKY_TARGETS_OF_MUTATED_TP53_DN, PEDERSEN_METASTASIS_BY_ERBB2_ISOFORM_1, BCL6B_TARGET_GENES, CREB3L4_TARGET_GENES, GREB1_TARGET_GENES, HES2_TARGET_GENES, KMT2D_TARGET_GENES, GSE11924_TFH_VS_TH1_CD4_TCELL_DN, MIR6782_5P

GO Biological Process (1): proteolysis (GO:0006508)

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 (2): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794)

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
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
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

969 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAPN8	GALNT9	Q9HCQ5	530
CAPN8	TPP1	O14773	452
CAPN8	CAPN9	O14815	439
CAPN8	PPT1	P50897	432
CAPN8	CAST	P20810	428
CAPN8	RILPL1	Q5EBL4	426
CAPN8	ECSCR	Q19T08	418
CAPN8	SUSD4	Q5VX71	413
CAPN8	TFF2	Q03403	405
CAPN8	DLGAP4	Q9Y2H0	404
CAPN8	KIRREL1	Q96J84	401
CAPN8	AK1	P00568	395
CAPN8	CCNB3	Q8WWL7	387
CAPN8	FAM20C	Q8IXL6	386
CAPN8	ATP4B	P51164	386

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CAPN8	CAPN1	psi-mi:“MI:0914”(association)	0.530
CAPN8	CAST	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): CAST (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), FNTB (Affinity Capture-MS), RPS3 (Affinity Capture-MS), CAPN8 (Affinity Capture-MS), CAST (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), KDM8 (Affinity Capture-MS), CAPN8 (Negative Genetic), CAPN8 (Negative Genetic), CAPN8 (Affinity Capture-RNA), CAPN8 (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

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	71
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
997085	GRCh37/hg19 1q41-42.12(chr1:223552998-224761890)	Pathogenic

SpliceAI

3381 predictions. Top by Δscore:

Variant	Effect	Δscore
1:223543162:TAGTT:T	acceptor_gain	1.0000
1:223543163:AGTT:A	acceptor_gain	1.0000
1:223543164:GTT:G	acceptor_gain	1.0000
1:223543165:TT:T	acceptor_gain	1.0000
1:223543166:TC:T	acceptor_loss	1.0000
1:223543167:C:CC	acceptor_gain	1.0000
1:223543167:CTAAA:C	acceptor_loss	1.0000
1:223543168:T:G	acceptor_loss	1.0000
1:223543176:C:CT	acceptor_gain	1.0000
1:223543176:C:T	acceptor_gain	1.0000
1:223543177:A:T	acceptor_gain	1.0000
1:223544061:ACT:A	donor_loss	1.0000
1:223544062:CTC:C	donor_loss	1.0000
1:223544063:TCACT:T	donor_loss	1.0000
1:223544064:CACT:C	donor_loss	1.0000
1:223544065:A:AC	donor_gain	1.0000
1:223544065:ACTG:A	donor_loss	1.0000
1:223544066:C:CA	donor_gain	1.0000
1:223544066:CTG:C	donor_gain	1.0000
1:223544066:CTGA:C	donor_gain	1.0000
1:223544185:T:G	acceptor_loss	1.0000
1:223619287:CCTTA:C	donor_loss	1.0000
1:223619288:CTTAC:C	donor_loss	1.0000
1:223619289:TTA:T	donor_loss	1.0000
1:223619290:TA:T	donor_loss	1.0000
1:223619291:ACC:A	donor_loss	1.0000
1:223619292:C:CT	donor_loss	1.0000
1:223622813:A:AC	donor_gain	1.0000
1:223622814:C:CC	donor_gain	1.0000
1:223622818:T:C	donor_gain	1.0000

AlphaMissense

4623 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:223620194:G:C	F324L	0.995
1:223620194:G:T	F324L	0.995
1:223620196:A:G	F324L	0.995
1:223619423:G:C	F335L	0.993
1:223619423:G:T	F335L	0.993
1:223619425:A:G	F335L	0.993
1:223609191:G:C	F499L	0.992
1:223609191:G:T	F499L	0.992
1:223609193:A:G	F499L	0.992
1:223622837:A:G	W293R	0.989
1:223622837:A:T	W293R	0.989
1:223665424:A:G	W75R	0.988
1:223665424:A:T	W75R	0.988
1:223628021:T:A	K183I	0.986
1:223628012:G:T	A186D	0.985
1:223627157:C:A	K187N	0.984
1:223627157:C:G	K187N	0.984
1:223625821:A:T	V266D	0.983
1:223628020:T:A	K183N	0.981
1:223628020:T:G	K183N	0.981
1:223628022:T:G	K183Q	0.981
1:223665494:G:C	F51L	0.981
1:223665494:G:T	F51L	0.981
1:223665496:A:G	F51L	0.981
1:223628040:A:G	W177R	0.980
1:223628040:A:T	W177R	0.980
1:223622835:C:A	W293C	0.978
1:223622835:C:G	W293C	0.978
1:223628023:C:A	E182D	0.978
1:223628023:C:G	E182D	0.978

dbSNP variants (sampled 300 via entrez): RS1000013546 (1:223609912 G>A), RS1000017501 (1:223649752 G>A,T), RS1000027434 (1:223653355 C>G,T), RS1000055583 (1:223655669 G>A), RS1000120633 (1:223665054 G>A), RS1000158255 (1:223627194 C>A,T), RS1000193637 (1:223651243 T>C), RS1000234785 (1:223656732 A>G), RS1000243476 (1:223554117 C>T), RS1000253193 (1:223644671 C>T), RS1000258939 (1:223661023 C>T), RS1000406088 (1:223629477 A>G), RS1000466413 (1:223645827 G>A), RS1000489097 (1:223655409 T>G), RS1000559282 (1:223657207 A>C)

Disease associations

OMIM: gene MIM:618777 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003938_3	Carotenoid levels (alpha-carotene)	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007893	alpha-carotene measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Valproic Acid	affects expression, decreases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
sotorasib	affects cotreatment, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
cylindrospermopsin	increases expression	1
NSC 689534	increases expression	1
trametinib	increases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Endosulfan	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Malathion	decreases expression	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Rotenone	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases expression	1
Permethrin	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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