CAPNS2

Summary

CAPNS2 (calpain small subunit 2, HGNC:16371) is a protein-coding gene on chromosome 16q12.2, encoding Calpain small subunit 2 (Q96L46). Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.

Enables calcium-dependent cysteine-type endopeptidase activity. Predicted to be located in cytosol and plasma membrane. Predicted to be part of calpain complex.

Source: NCBI Gene 84290 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_032330

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16371
Approved symbol	CAPNS2
Name	calpain small subunit 2
Location	16q12.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC12536, MGC14804
Ensembl gene	ENSG00000256812
Ensembl biotype	protein_coding
OMIM	616767
Entrez	84290

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000457326

RefSeq mRNA: 1 — MANE Select: NM_032330 NM_032330

CCDS: CCDS54010

Canonical transcript exons

ENST00000457326 — 1 exons

Exon	Start	End
ENSE00002251412	55566684	55567687

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 97.69.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0632 / max 162.9762, expressed in 93 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154171	1.0467	91
154172	0.0165	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	97.69	gold quality
oral cavity	UBERON:0000167	97.04	gold quality
upper arm skin	UBERON:0004263	96.99	gold quality
upper leg skin	UBERON:0004262	96.73	gold quality
skin of abdomen	UBERON:0001416	96.55	gold quality
gingiva	UBERON:0001828	96.44	gold quality
gingival epithelium	UBERON:0001949	96.27	gold quality
zone of skin	UBERON:0000014	95.82	gold quality
skin of leg	UBERON:0001511	95.45	gold quality
esophagus mucosa	UBERON:0002469	95.00	gold quality
palpebral conjunctiva	UBERON:0001812	94.32	gold quality
skin of hip	UBERON:0001554	94.24	gold quality
mammalian vulva	UBERON:0000997	93.15	gold quality
lower esophagus mucosa	UBERON:0035834	93.14	gold quality
penis	UBERON:0000989	91.74	gold quality
pharyngeal mucosa	UBERON:0000355	89.65	gold quality
nipple	UBERON:0002030	84.68	gold quality
vagina	UBERON:0000996	83.56	gold quality
body of tongue	UBERON:0011876	80.15	gold quality
epithelium of nasopharynx	UBERON:0001951	77.32	silver quality
urinary bladder	UBERON:0001255	74.82	gold quality
tonsil	UBERON:0002372	74.67	gold quality
tongue	UBERON:0001723	72.56	gold quality
amniotic fluid	UBERON:0000173	72.11	gold quality
tibialis anterior	UBERON:0001385	70.54	silver quality
esophagus	UBERON:0001043	70.28	gold quality
ileal mucosa	UBERON:0000331	69.52	silver quality
urethra	UBERON:0000057	67.93	gold quality
pancreatic ductal cell	CL:0002079	67.17	silver quality
superior surface of tongue	UBERON:0007371	66.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting CAPNS2, 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-3617-3P	99.98	67.86	918
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-135A-2-3P	98.40	66.74	442
HSA-MIR-135B-3P	98.40	67.35	426
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-383-5P	96.86	67.55	820
HSA-MIR-4772-5P	95.60	68.04	617

Literature-anchored findings (GeneRIF, showing 1)

• Our results indicate that prolonged calpain expression in resident brain cells (neurons, glial and endothelial cells) plays an important role in neuronal degeneration following traumatic brain injury. (PMID:23390828)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	capn12	ENSDARG00000010758
danio_rerio	zgc:85932	ENSDARG00000098239
mus_musculus	Capns2	ENSMUSG00000078144
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), CAPN8 (ENSG00000203697), CAPN14 (ENSG00000214711), PDCD6 (ENSG00000249915)

Protein

Protein identifiers

Calpain small subunit 2 — Q96L46 (reviewed: Q96L46)

Alternative names: Calcium-dependent protease small subunit 2

All UniProt accessions (1): Q96L46

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. This small subunit may act as a tissue-specific chaperone of the large subunit, possibly by helping it fold into its correct conformation for activity.

Subunit / interactions. Heterodimer of a large (catalytic) and a small (regulatory) subunit.

Subcellular location. Cytoplasm. Cell membrane.

RefSeq proteins (1): NP_115706* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily

Pfam: PF13833

UniProt features (19 total): binding site 13, domain 4, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L46-F1	76.67	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (13): 134; 136; 138; 143; 162; 164; 166; 205; 89; 92; 94; 117 …

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells

MSigDB gene sets: 73 (showing top): BIOCARTA_P35ALZHEIMERS_PATHWAY, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, BIOCARTA_UCALPAIN_PATHWAY, MODULE_48, MODULE_95, YNGTTNNNATT_UNKNOWN, AR_Q2, GOMF_PEPTIDASE_ACTIVITY, EVI1_02, GOMF_CALCIUM_DEPENDENT_CYSTEINE_TYPE_ENDOPEPTIDASE_ACTIVITY, CHEN_METABOLIC_SYNDROM_NETWORK, GOCC_PEPTIDASE_COMPLEX, GOCC_ENDOPEPTIDASE_COMPLEX, MODULE_163, REACTOME_CELLULAR_RESPONSES_TO_STIMULI

GO Biological Process (0):

GO Molecular Function (4): calcium-dependent cysteine-type endopeptidase activity (GO:0004198), calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): cytosol (GO:0005829), plasma membrane (GO:0005886), calpain complex (GO:0110158), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Response of endothelial cells to shear stress	2
Extracellular matrix organization	1
Neurodegenerative Diseases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
cysteine-type endopeptidase activity	1
metal ion binding	1
binding	1
cation binding	1
membrane	1
cell periphery	1
caspase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAPNS2	CAPN7	Q9Y6W3	543
CAPNS2	MBIP	Q9NS73	538
CAPNS2	NETO1	Q8TDF5	515
CAPNS2	PRDM11	Q9NQV5	507
CAPNS2	LPCAT2	Q7L5N7	505
CAPNS2	FBXO15	Q8NCQ5	479
CAPNS2	PDE8B	O95263	478
CAPNS2	ITPK1	Q13572	465
CAPNS2	AADAT	Q8N5Z0	420
CAPNS2	CAPN5	O15484	419
CAPNS2	PDE10A	Q9Y233	418
CAPNS2	SASH1	O94885	397
CAPNS2	TMEM196	Q5HYL7	386
CAPNS2	CAST	P20810	372
CAPNS2	FOXE1	O00358	369

IntAct

66 interactions, top by confidence:

A	B	Type	Score
CAPN1	CAPNS1	psi-mi:“MI:0914”(association)	0.840
SRP9	SRP72	psi-mi:“MI:0914”(association)	0.730
CAPNS2	CAPN1	psi-mi:“MI:0914”(association)	0.640
CMTM5	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
PHACTR3	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
PRPF31	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
OXNAD1	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
PPIC	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
RIN1	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
ARMC10	CAPNS2	psi-mi:“MI:0915”(physical association)	0.560
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
GMCL1	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
DNAAF19	KLK10	psi-mi:“MI:0914”(association)	0.530
CAPNS2	CAPNS1	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
ZIC1	CTSV	psi-mi:“MI:0914”(association)	0.530
ZIC1	IMPA2	psi-mi:“MI:0914”(association)	0.350
RBFOX1	IMPA2	psi-mi:“MI:0914”(association)	0.350
GLYR1	FNTB	psi-mi:“MI:0914”(association)	0.350
KLHL11	PIPSL	psi-mi:“MI:0914”(association)	0.350
ST6GALNAC6	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (67): ACTA2 (Affinity Capture-MS), CAPNS1 (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), CAST (Affinity Capture-MS), LIX1L (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), LIX1L (Affinity Capture-MS), CAST (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I6A2H6, A4IG32, A5D7A0, B1H2N3, D2HZB0, F1LNJ2, O70585, O75643, O88456, P04574, P04632, P06813, P07090, P13135, P22676, P23092, P46940, P47728, Q08331, Q0IIL1, Q1RMX9, Q3ZBY3, Q4FZY0, Q4KUS2, Q4R518, Q5PPL2, Q5RDF9, Q5RDI4, Q62768, Q64537, Q6NWD4, Q6P4T2, Q6P6Q9, Q6PHS6, Q7KZ85, Q86XE3, Q8C079, Q8VCX5, Q8WWF8, Q96C19

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

371 predictions. Top by Δscore:

Variant	Effect	Δscore
16:55567608:C:T	donor_gain	0.9600
16:55566711:T:G	acceptor_gain	0.9400
16:55566768:AAAG:A	acceptor_gain	0.8700
16:55566769:A:G	acceptor_gain	0.8600
16:55567566:ACAC:A	donor_gain	0.7600
16:55566768:A:AG	acceptor_gain	0.7500
16:55567342:C:CA	acceptor_gain	0.7000
16:55567388:GCT:G	acceptor_gain	0.6800
16:55567364:A:G	donor_gain	0.6700
16:55567544:A:T	donor_gain	0.6700
16:55567403:T:TA	acceptor_gain	0.6600
16:55567673:A:G	donor_gain	0.6600
16:55567385:T:G	acceptor_gain	0.6500
16:55567543:GAC:G	donor_gain	0.6500
16:55567561:GCT:G	donor_gain	0.6500
16:55567535:G:GT	donor_gain	0.6400
16:55566767:CAA:C	acceptor_gain	0.6000
16:55566768:AAA:A	acceptor_gain	0.6000
16:55566769:A:AC	acceptor_gain	0.6000
16:55567538:G:GT	donor_gain	0.6000
16:55566710:A:AG	acceptor_gain	0.5800
16:55567539:A:T	donor_gain	0.5800
16:55567516:G:GT	donor_gain	0.5600
16:55566766:G:T	acceptor_gain	0.5500
16:55567404:G:A	acceptor_gain	0.5500
16:55567427:A:G	acceptor_gain	0.5500
16:55566857:G:GT	donor_gain	0.5400
16:55566767:CAAAG:C	acceptor_gain	0.5300
16:55567309:C:G	donor_gain	0.5300
16:55567387:A:AG	acceptor_gain	0.5300

AlphaMissense

1631 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:55567009:T:C	F85L	0.996
16:55567011:T:A	F85L	0.996
16:55567011:T:G	F85L	0.996
16:55567128:C:G	C124W	0.995
16:55567216:T:A	W154R	0.995
16:55567216:T:C	W154R	0.995
16:55567423:T:C	F223L	0.995
16:55567425:C:A	F223L	0.995
16:55567425:C:G	F223L	0.995
16:55567010:T:C	F85S	0.994
16:55567112:T:C	F119S	0.993
16:55567304:T:C	F183S	0.993
16:55567477:T:A	W241R	0.993
16:55567477:T:C	W241R	0.993
16:55567055:T:C	L100P	0.992
16:55567127:G:A	C124Y	0.992
16:55567132:A:C	S126R	0.992
16:55567134:C:A	S126R	0.992
16:55567134:C:G	S126R	0.992
16:55567186:T:C	F144L	0.992
16:55567188:T:A	F144L	0.992
16:55567188:T:G	F144L	0.992
16:55567198:T:A	W148R	0.992
16:55567198:T:C	W148R	0.992
16:55567126:T:C	C124R	0.991
16:55567130:G:C	R125P	0.991
16:55567303:T:C	F183L	0.991
16:55567305:C:A	F183L	0.991
16:55567305:C:G	F183L	0.991
16:55567390:T:C	C212R	0.990

dbSNP variants (sampled 300 via entrez): RS1001906948 (16:55567961 T>C), RS1004190041 (16:55567540 C>G,T), RS1005039568 (16:55565853 A>G,T), RS1006044092 (16:55567521 C>G,T), RS1008988575 (16:55565361 T>C), RS1012235071 (16:55565922 G>C,T), RS1012643350 (16:55564803 C>T), RS1013314022 (16:55567927 A>G), RS1017744425 (16:55564905 A>T), RS1019167332 (16:55566299 A>G), RS1021384992 (16:55564804 G>A,T), RS1023724854 (16:55566222 T>A), RS1024027328 (16:55565970 A>G,T), RS1024615553 (16:55567584 T>C), RS1025149319 (16:55567931 A>G)

Disease associations

OMIM: gene MIM:616767 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001856_19	Thyroid hormone levels	5.000000e-08
GCST001856_23	Thyroid hormone levels	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol F	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arbutin	increases expression	1
Copper	affects cotreatment, decreases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Mustard Gas	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	increases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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