CPNE4

Summary

CPNE4 (copine 4, HGNC:2317) is a protein-coding gene on chromosome 3q22.1, encoding Copine-4 (Q96A23). Probable calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes.

This gene belongs to the highly conserved copine family. It encodes a calcium-dependent, phospholipid-binding protein, which may be involved in membrane trafficking, mitogenesis and development. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 131034 — RefSeq curated summary.

At a glance

• GWAS associations: 27
• Clinical variants (ClinVar): 58 total
• Druggable target: yes
• MANE Select transcript: NM_130808

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2317
Approved symbol	CPNE4
Name	copine 4
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	COPN4, CPN4
Ensembl gene	ENSG00000196353
Ensembl biotype	protein_coding
OMIM	604208
Entrez	131034

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 18 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000429747, ENST00000502818, ENST00000503204, ENST00000505331, ENST00000505881, ENST00000505957, ENST00000506687, ENST00000511604, ENST00000512055, ENST00000512332, ENST00000514439, ENST00000514999, ENST00000515418, ENST00000617767, ENST00000886212, ENST00000886213, ENST00000933671, ENST00000933672, ENST00000943028, ENST00000943029, ENST00000943030, ENST00000943031, ENST00000943032

RefSeq mRNA: 5 — MANE Select: NM_130808 NM_001289112, NM_001388326, NM_001388327, NM_130808, NM_153429

CCDS: CCDS3072, CCDS75010

Canonical transcript exons

ENST00000429747 — 16 exons

Exon	Start	End
ENSE00002296189	131723446	131723625
ENSE00003461318	131564216	131564349
ENSE00003499677	131542557	131542793
ENSE00003519746	131581579	131581665
ENSE00003536115	131905264	131905444
ENSE00003550568	131575071	131575130
ENSE00003556691	131699909	131699980
ENSE00003570701	131669675	131669764
ENSE00003586542	131549947	131550080
ENSE00003590626	131587484	131587582
ENSE00003637717	131555497	131555551
ENSE00003662998	131685875	131685958
ENSE00003663771	131552440	131552491
ENSE00003787748	131696542	131696616
ENSE00003921309	132034567	132035014
ENSE00003921880	131533569	131535329

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 97.72.

FANTOM5 (CAGE): breadth broad, TPM avg 3.9116 / max 275.8935, expressed in 409 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44607	2.9072	345
44606	0.4555	143
44605	0.1579	67
44604	0.0994	52
44609	0.0934	35
44620	0.0755	36
44603	0.0601	16
44608	0.0327	17
44610	0.0158	7
44611	0.0091	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.72	gold quality
left ventricle myocardium	UBERON:0006566	95.72	gold quality
endothelial cell	CL:0000115	93.98	gold quality
primary visual cortex	UBERON:0002436	92.72	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.53	gold quality
palpebral conjunctiva	UBERON:0001812	90.44	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.74	gold quality
occipital lobe	UBERON:0002021	89.18	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.06	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.96	gold quality
heart right ventricle	UBERON:0002080	88.86	gold quality
prefrontal cortex	UBERON:0000451	88.69	gold quality
prostate gland	UBERON:0002367	88.69	gold quality
Ammon’s horn	UBERON:0001954	88.11	gold quality
cortical plate	UBERON:0005343	87.96	gold quality
anterior cingulate cortex	UBERON:0009835	87.96	gold quality
cerebral cortex	UBERON:0000956	87.64	gold quality
superior frontal gyrus	UBERON:0002661	87.61	gold quality
neocortex	UBERON:0001950	87.36	gold quality
frontal cortex	UBERON:0001870	87.30	gold quality
postcentral gyrus	UBERON:0002581	86.91	gold quality
dorsal root ganglion	UBERON:0000044	86.09	gold quality
heart left ventricle	UBERON:0002084	85.80	gold quality
cardiac ventricle	UBERON:0002082	85.78	gold quality
parietal lobe	UBERON:0001872	85.71	gold quality
right frontal lobe	UBERON:0002810	85.23	gold quality
amygdala	UBERON:0001876	84.70	gold quality
entorhinal cortex	UBERON:0002728	84.68	gold quality
middle temporal gyrus	UBERON:0002771	84.48	gold quality
temporal lobe	UBERON:0001871	84.43	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	677.82
E-HCAD-25	yes	650.80
E-HCAD-35	yes	71.56
E-ANND-3	yes	6.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting CPNE4, 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-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4673	100.00	66.64	1490
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 3)

• Cloning, molecular characterization, and expression analysis. May have an important role to play in prostate regulation and development. (PMID:12670487)
• Single nucleotide polymorphisms in CPEN4 gene is associated with Coronary Artery Disease. (PMID:25328121)
• Molecular studies into cell biological role of Copine-4 in Retinal Ganglion Cells. (PMID:34847148)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpne4a	ENSDARG00000101095
danio_rerio	cpne4b	ENSDARG00000104254
mus_musculus	Cpne4	ENSMUSG00000032564
rattus_norvegicus	Cpne4	ENSRNOG00000026577
caenorhabditis_elegans		WBGENE00001577
caenorhabditis_elegans		WBGENE00006441
caenorhabditis_elegans		WBGENE00012128
caenorhabditis_elegans		WBGENE00015061

Paralogs (8): CPNE3 (ENSG00000085719), CPNE6 (ENSG00000100884), CPNE5 (ENSG00000124772), CPNE8 (ENSG00000139117), CPNE2 (ENSG00000140848), CPNE9 (ENSG00000144550), CPNE7 (ENSG00000178773), CPNE1 (ENSG00000214078)

Protein

Protein identifiers

Copine-4 — Q96A23 (reviewed: Q96A23)

Alternative names: Copine IV, Copine-8

All UniProt accessions (4): D6RCT2, D6RFY4, D6RI99, Q96A23

UniProt curated annotations — full annotation on UniProt →

Function. Probable calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes.

Subunit / interactions. Interacts (via VWFA domain) with ACTB, BCOR, BICD2, CCDC22, CDC42BPB, CEP162, MYCBP2, NONO, PDCD6, PITPNM2, RDX, SKIL, SKT, SPTBN1, UBE2O and WTAP.

Tissue specificity. Widely expressed. Expressed strongly in the brain, heart and prostate. Expressed strongly in peripheral blood leukocytes.

Similarity. Belongs to the copine family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96A23-1	1	yes
Q96A23-2	2

RefSeq proteins (5): NP_001276041, NP_001375255, NP_001375256, NP_570720, NP_702907 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR002035	VWF_A	Domain
IPR010734	Copine_C	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR037768	C2B_Copine	Domain
IPR045052	Copine	Family

Pfam: PF00168, PF07002

UniProt features (13 total): binding site 8, domain 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96A23-F1	87.42	0.67

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 (8): 234; 240; 170; 170; 176; 232; 232; 234

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 110 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, GOZGIT_ESR1_TARGETS_DN, GOBP_RESPONSE_TO_METAL_ION, AACTTT_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_CALCIUM_ION, USF_02, FUJII_YBX1_TARGETS_UP, chr3q22, MODULE_207, ATF_01, GOBP_RESPONSE_TO_CALCIUM_ION, GOCC_SYNAPSE, THUM_SYSTOLIC_HEART_FAILURE_DN, GOMF_LIPID_BINDING

GO Biological Process (1): cellular response to calcium ion (GO:0071277)

GO Molecular Function (3): calcium-dependent phospholipid binding (GO:0005544), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to calcium ion	1
cellular response to metal ion	1
phospholipid binding	1
cation binding	1
binding	1
membrane	1
cell periphery	1
extracellular vesicle	1
synapse	1
cell junction	1

Protein interactions and networks

STRING

966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPNE4	TMTC4	Q5T4D3	488
CPNE4	FIGN	Q5HY92	474
CPNE4	PCCB	P05166	424
CPNE4	FRMD4B	Q9Y2L6	406
CPNE4	NRXN3	Q9Y4C0	392
CPNE4	PPP1R1C	Q8WVI7	383
CPNE4	GFAP	P14136	380
CPNE4	CTXND1	A0A1B0GTU2	377
CPNE4	DDN	O94850	366
CPNE4	LRRC10B	A6NIK2	359
CPNE4	KBTBD12	Q3ZCT8	359
CPNE4	FLOT1	O75955	352
CPNE4	THY1	P04216	348
CPNE4	ECRG4	Q9H1Z8	347
CPNE4	TIAM1	Q13009	336

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ANKRD49	CSNK1E	psi-mi:“MI:0914”(association)	0.640
ECE1	CPNE4	psi-mi:“MI:0915”(physical association)	0.370
CPNE4	CPNE6	psi-mi:“MI:0914”(association)	0.350
CPNE4	JMY	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): CPNE4 (Reconstituted Complex), Pdcd6 (Two-hybrid), CPNE4 (Affinity Capture-MS), HIST1H1A (Affinity Capture-MS), EBF3 (Affinity Capture-MS), BAHCC1 (Affinity Capture-MS), CPNE6 (Affinity Capture-MS), RABEP2 (Affinity Capture-MS), RPS27A (Affinity Capture-MS), RPL26L1 (Affinity Capture-MS), RGPD5 (Affinity Capture-MS), GTF3C2 (Affinity Capture-MS), UTRN (Affinity Capture-MS), CPNE4 (Affinity Capture-MS), WHSC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PPP7, F1NV61, O01382, O02002, O08738, O35397, O89094, O89110, P29452, P29594, P31944, P42574, P42575, P43527, P55211, P55212, P55213, P55215, P55865, P55866, P55867, P70343, P70677, P89116, Q08DY9, Q0IIM3, Q14344, Q14790, Q153Z0, Q2PFV2, Q3T0P5, Q504J1, Q5IS54, Q5IS99, Q60431, Q60446, Q61699, Q66HA8, Q8BLR2, Q8C3Q9

Diamond homologs: A8WMY4, D4A1R8, H1UBN0, H2KYS8, O75131, O95741, P59108, Q08DB4, Q0VE82, Q1RLL3, Q1ZXB3, Q2KHY1, Q54FY7, Q54P51, Q55GG1, Q5BJS7, Q5R4W6, Q5RAE1, Q5S1W2, Q5XQC7, Q7YXU4, Q86K21, Q86YQ8, Q8BLR2, Q8BT60, Q8C166, Q8IYJ1, Q8JZW4, Q941L3, Q96A23, Q96FN4, Q99829, Q9DC53, Q9HCH3, Q9UBL6, Q9XUB9, Q9Z140, A0JJX5, Q09219, Q12466

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4872 predictions. Top by Δscore:

Variant	Effect	Δscore
3:131549941:CCTTA:C	donor_loss	1.0000
3:131549942:CTT:C	donor_loss	1.0000
3:131549943:TTACC:T	donor_loss	1.0000
3:131549944:TACCG:T	donor_loss	1.0000
3:131549945:A:AC	donor_gain	1.0000
3:131549945:ACC:A	donor_loss	1.0000
3:131549946:C:CC	donor_gain	1.0000
3:131549946:C:G	donor_loss	1.0000
3:131549954:T:TA	donor_gain	1.0000
3:131555559:CAAAA:C	acceptor_gain	1.0000
3:131564346:CTAC:C	acceptor_gain	1.0000
3:131564348:ACC:A	acceptor_loss	1.0000
3:131564350:CTA:C	acceptor_loss	1.0000
3:131575069:A:AC	donor_gain	1.0000
3:131575070:C:CC	donor_gain	1.0000
3:131581574:CATA:C	donor_loss	1.0000
3:131581575:ATACC:A	donor_loss	1.0000
3:131581576:TA:T	donor_loss	1.0000
3:131581666:C:CA	acceptor_loss	1.0000
3:131581667:T:G	acceptor_loss	1.0000
3:131685869:TCTTA:T	donor_loss	1.0000
3:131685870:CTTAC:C	donor_loss	1.0000
3:131685871:TTACC:T	donor_loss	1.0000
3:131685872:TA:T	donor_loss	1.0000
3:131685873:A:C	donor_loss	1.0000
3:131685874:C:CG	donor_loss	1.0000
3:131685957:TC:T	acceptor_gain	1.0000
3:131685958:CC:C	acceptor_gain	1.0000
3:131685960:T:C	acceptor_loss	1.0000
3:131696536:CTTTA:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008961 (3:131975275 C>T), RS1000010645 (3:131698864 C>T), RS1000015986 (3:131816784 C>G,T), RS1000035412 (3:131975434 T>C), RS1000042796 (3:131856847 C>A), RS1000045876 (3:131566265 T>C,G), RS1000051874 (3:131817071 G>A), RS1000065050 (3:131582941 T>C), RS1000072414 (3:131941371 A>C), RS1000073266 (3:131770699 C>T), RS1000076608 (3:131784682 T>C), RS1000079581 (3:131712668 C>A), RS1000080697 (3:131699174 C>A,G), RS1000084976 (3:132004738 T>A), RS1000087823 (3:131842214 A>C,G)

Disease associations

OMIM: gene MIM:604208 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST001059_14	Neutrophil count	2.000000e-07
GCST001664_3	Amyotrophic lateral sclerosis	7.000000e-06
GCST002759_10	Motion sickness	1.000000e-14
GCST002783_254	Body mass index	7.000000e-07
GCST002783_433	Body mass index	2.000000e-06
GCST003473_9	Aggressiveness in attention deficit hyperactivity disorder	4.000000e-06
GCST003560_11	Coronary artery aneurysm in Kawasaki disease	3.000000e-06
GCST004250_51	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	2.000000e-06
GCST004571_4	Iron status biomarkers (total iron binding capacity)	3.000000e-07
GCST004572_14	Iron status biomarkers (transferrin saturation)	3.000000e-07
GCST004792_1	Amyotrophic lateral sclerosis in C9orf72 mutation positive individuals	4.000000e-07
GCST004792_6	Amyotrophic lateral sclerosis in C9orf72 mutation positive individuals	9.000000e-06
GCST004904_69	Body mass index	3.000000e-08
GCST005576_8	Intracranial aneurysm	3.000000e-06
GCST009107_17	Body mass index variance	2.000000e-12
GCST009121_8	Body mass index	3.000000e-17
GCST009532_15	Circulating leptin levels in high cardiovascular risk	9.000000e-08
GCST009602_69	Metabolic syndrome	7.000000e-09
GCST010242_150	HDL cholesterol levels	5.000000e-12
GCST010988_113	Adult body size	6.000000e-09
GCST010988_114	Adult body size	3.000000e-23
GCST010989_230	Body size at age 10	3.000000e-08
GCST010989_231	Body size at age 10	2.000000e-11
GCST012381_2	Eosinophilic esophagitis	4.000000e-08
GCST012488_2	L1-L4 bone mineral density x serum urate levels interaction	6.000000e-07
GCST012488_39	L1-L4 bone mineral density x serum urate levels interaction	2.000000e-06
GCST90011893_1	Retinitis pigmentosa	6.000000e-06

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0006928	motion sickness
EFO:0004340	body mass index
EFO:0007965	response to combination chemotherapy
EFO:0006334	total iron binding capacity
EFO:0005000	leptin measurement
EFO:0000195	metabolic syndrome
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066496 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.06	Kd	8.672	nM	CHEMBL3752910
8.06	ED50	8.672	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149843: Binding affinity to human CPNE4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0087	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
clothianidin	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	decreases expression	1
Silicon Dioxide	decreases expression	1
Triclosan	decreases expression	1
Cyclosporine	increases expression	1
Uranium Compounds	decreases expression	1
Cadmium Chloride	increases abundance, decreases 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
CHEMBL5652885	Binding	Binding affinity to human CPNE4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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