RCAN2

Summary

RCAN2 (regulator of calcineurin 2, HGNC:3041) is a protein-coding gene on chromosome 6p12.3, encoding Calcipressin-2 (Q14206). Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A.

This gene encodes a member of the regulator of calcineurin (RCAN) protein family. These proteins play a role in many physiological processes by binding to the catalytic domain of calcineurin A, inhibiting calcineurin-mediated nuclear translocation of the transcription factor NFATC1. Expression of this gene in skin fibroblasts is upregulated by thyroid hormone, and the encoded protein may also play a role in endothelial cell function and angiogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 10231 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_001251974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3041
Approved symbol	RCAN2
Name	regulator of calcineurin 2
Location	6p12.3
Locus type	gene with protein product
Status	Approved
Aliases	ZAKI-4
Ensembl gene	ENSG00000172348
Ensembl biotype	protein_coding
OMIM	604876
Entrez	10231

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000306764, ENST00000330430, ENST00000371374

RefSeq mRNA: 3 — MANE Select: NM_001251974 NM_001251973, NM_001251974, NM_005822

CCDS: CCDS43469, CCDS59023

Canonical transcript exons

ENST00000371374 — 5 exons

Exon	Start	End
ENSE00001139858	46246748	46246919
ENSE00001139866	46248723	46248896
ENSE00001455084	46491173	46491449
ENSE00001455094	46456752	46456978
ENSE00003733427	46220736	46223301

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5683 / max 568.1190, expressed in 978 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73826	6.4156	527
73841	5.2013	697
73837	2.2470	207
73839	1.2013	251
73842	0.6884	270
73827	0.5798	206
73844	0.5165	163
73825	0.3689	110
73830	0.2127	119
73840	0.2082	110

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.89	gold quality
substantia nigra pars compacta	UBERON:0001965	99.81	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.66	gold quality
pons	UBERON:0000988	99.57	gold quality
heart right ventricle	UBERON:0002080	99.53	gold quality
middle temporal gyrus	UBERON:0002771	99.37	gold quality
endothelial cell	CL:0000115	99.28	gold quality
lateral globus pallidus	UBERON:0002476	99.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.19	gold quality
superior vestibular nucleus	UBERON:0007227	99.09	gold quality
mucosa of stomach	UBERON:0001199	99.05	gold quality
blood vessel layer	UBERON:0004797	98.99	gold quality
left ventricle myocardium	UBERON:0006566	98.98	gold quality
ventral tegmental area	UBERON:0002691	98.89	gold quality
superior frontal gyrus	UBERON:0002661	98.81	gold quality
parietal lobe	UBERON:0001872	98.80	gold quality
urethra	UBERON:0000057	98.76	gold quality
orbitofrontal cortex	UBERON:0004167	98.71	gold quality
postcentral gyrus	UBERON:0002581	98.70	gold quality
inferior olivary complex	UBERON:0002127	98.62	gold quality
myocardium	UBERON:0002349	98.62	gold quality
saphenous vein	UBERON:0007318	98.60	gold quality
occipital lobe	UBERON:0002021	98.59	gold quality
primary visual cortex	UBERON:0002436	98.58	gold quality
medulla oblongata	UBERON:0001896	98.48	gold quality
popliteal artery	UBERON:0002250	98.45	gold quality
tibial artery	UBERON:0007610	98.45	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.41	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.34	gold quality
dorsal root ganglion	UBERON:0000044	98.30	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	3128.67
E-GEOD-135922	yes	49.15
E-CURD-119	yes	47.05
E-MTAB-10287	yes	45.00
E-GEOD-93593	yes	7.78
E-HCAD-25	yes	7.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

233 targeting RCAN2, 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-6798-5P	100.00	65.77	699
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-513A-5P	100.00	69.77	2465
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-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6778-3P	99.96	67.29	2693
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-570-3P	99.96	72.41	4910
HSA-MIR-128-3P	99.95	71.17	2484

Literature-anchored findings (GeneRIF, showing 12)

• the expression of ZAKI-4 isoforms is subjected to distinct hormonal as well as tissue-specific regulation, constituting a complex signalling network through inhibition of calcineurin. (PMID:12102656)
• DSCR1-L1 is constitutively expressed in endothelial cells and acts similar to DSCR1 in inhibiting calcineurin activity and restraining VEGF-mediated angiogenesis. (PMID:17610901)
• our data have elucidated the molecular and cellular mechanism whereby PGF(2alpha) regulates CXCL8 expression via the FP receptor in endometrial adenocarcinomas and have highlighted RCAN1-4 as a negative regulator of CXCL8 expression (PMID:19819266)
• RCAN2 expression is upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Data define RCAN2 as a regulator of cilia function that can compensate for the loss of giantin function. (PMID:29643119)
• These results suggest that RCAN2 is involved in tumour progression and is an independent prognostic classifier in patients with gastric cancer (PMID:30307052)
• YAP1, TEF3 and DSCR1-1L is a common signaling pathway downstream of several angiogenic factors that regulates angiogenesis. (PMID:31733305)
• A novel transcriptional complex on the VE-cadherin promoter regulated the downregulation of VE-cadherin in the Down Syndrome Candidate Region 1 isoform 1L-mediated angiogenesis. (PMID:34146582)
• Association Between Circulating Regulator of Calcineurin 2 Concentrations With Overweight and Obesity. (PMID:35733783)
• USP7-mediated JUND suppresses RCAN2 transcription and elevates NFATC1 to enhance stem cell property in colorectal cancer. (PMID:37535148)
• CircIQGAP1 regulates RCAN1 and RCAN2 through the mechanism of ceRNA and promotes the growth of malignant glioma. (PMID:37918583)
• TMB Signature-Related RCAN2 Promotes Apoptosis by Upregulating EHF/DR5 Pathway in Hepatocellular Carcinoma. (PMID:39082336)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rcan2	ENSDARG00000021869
mus_musculus	Rcan2	ENSMUSG00000039601
rattus_norvegicus	Rcan2	ENSRNOG00000010350
drosophila_melanogaster	sra	FBGN0086370
caenorhabditis_elegans		WBGENE00004321

Paralogs (2): RCAN3 (ENSG00000117602), RCAN1 (ENSG00000159200)

Protein

Protein identifiers

Calcipressin-2 — Q14206 (reviewed: Q14206)

Alternative names: Down syndrome candidate region 1-like 1, Myocyte-enriched calcineurin-interacting protein 2, Regulator of calcineurin 2, Thyroid hormone-responsive protein ZAKI-4

All UniProt accessions (1): Q14206

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A. Could play a role during central nervous system development.

Tissue specificity. Expressed in fibroblasts, heart, brain, liver, and skeletal muscle but not in placenta, lung, kidney and pancreas.

Induction. By thyroid hormone.

Similarity. Belongs to the RCAN family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14206-1	1, ZAKI-4 alpha	yes
Q14206-2	2, ZAKI-4 beta

RefSeq proteins (3): NP_001238902, NP_001238903, NP_005813 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006931	Calcipressin	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034919	RCAN2_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF04847

UniProt features (6 total): sequence conflict 2, chain 1, region of interest 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14206-F1	79.87	0.41

Functional residue map

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

Post-translational modifications (1): 167

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 214 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, PID_NFAT_3PATHWAY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01, CACCAGC_MIR138, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, MODULE_66, BROWNE_HCMV_INFECTION_48HR_DN, chr6p12, OCT1_03

GO Biological Process (7): response to oxidative stress (GO:0006979), Notch signaling pathway (GO:0007219), short-term memory (GO:0007614), calcium-mediated signaling (GO:0019722), locomotion involved in locomotory behavior (GO:0031987), calcineurin-NFAT signaling cascade (GO:0033173), response to stress (GO:0006950)

GO Molecular Function (2): nucleic acid binding (GO:0003676), calcium-dependent protein serine/threonine phosphatase regulator activity (GO:0008597)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	1
cell surface receptor signaling pathway	1
memory	1
intracellular signaling cassette	1
locomotory behavior	1
locomotion	1
calcineurin-mediated signaling	1
response to stimulus	1
binding	1
calcium-dependent protein serine/threonine phosphatase activity	1
protein phosphatase regulator activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RCAN2	PPP3CA	Q08209	612
RCAN2	PPP3CB	P16298	572
RCAN2	NFATC1	O95644	570
RCAN2	OR52E5	Q8NH55	540
RCAN2	SIK2	Q9H0K1	497
RCAN2	F2R	P25116	492
RCAN2	TNNI3	P19429	471
RCAN2	VSTM2L	Q96N03	445
RCAN2	GATA2	P23769	439
RCAN2	DYRK1A	Q13627	438
RCAN2	PTTG2	Q9NZH5	435
RCAN2	ZNF385B	Q569K4	432
RCAN2	ANLN	Q9NQW6	428
RCAN2	CPNE8	Q86YQ8	427
RCAN2	SPON1	Q9HCB6	425

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ELOC	RCAN2	psi-mi:“MI:0915”(physical association)	0.370
ECE1	RCAN2	psi-mi:“MI:0915”(physical association)	0.370
RCAN2	HSBP1	psi-mi:“MI:0914”(association)	0.350
RCAN2	PPP3CB	psi-mi:“MI:0914”(association)	0.350
PPP3CC	MAP2K7	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): PPP3CB (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), GSTZ1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), ZG16B (Affinity Capture-MS), AMY1C (Affinity Capture-MS), SERPINA12 (Affinity Capture-MS), MUC7 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), GSK3B (Affinity Capture-MS), GSK3A (Affinity Capture-MS), CRNN (Affinity Capture-MS), CST4 (Affinity Capture-MS), CST2 (Affinity Capture-MS)

ESM2 similar proteins: A2AHJ4, A5A6I8, A7MBL8, O08874, O14795, O35099, O35847, P0C606, P0C7A6, P53805, Q14206, Q16513, Q28C34, Q2KIA1, Q3ZC15, Q4R4P5, Q4R8N2, Q5JSJ4, Q5RE25, Q5RES7, Q5TKA1, Q5ZJV6, Q5ZL38, Q62769, Q6AYF1, Q6IN33, Q6NRD0, Q6RI45, Q6ZN16, Q7ZYD9, Q8BKH7, Q8BND4, Q8BPM2, Q8C735, Q8CH27, Q8IVH8, Q8IZC4, Q8N6S4, Q8VDD9, Q8WWQ0

Diamond homologs: A5A6I8, O35847, P53805, P53806, Q14206, Q2KIA1, Q3ZBP4, Q3ZC15, Q4R4P5, Q5RE25, Q5RES7, Q5ZJV6, Q6IN33, Q6XXM7, Q8CH27, Q9JHG2, Q9JHG6, Q9JKK0, Q9UKA8, Q9XZL8, Q09791

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1015 predictions. Top by Δscore:

Variant	Effect	Δscore
6:46223302:C:CC	acceptor_gain	1.0000
6:46246742:GCTTA:G	donor_loss	1.0000
6:46246743:CTTA:C	donor_loss	1.0000
6:46246744:TTA:T	donor_loss	1.0000
6:46246745:TA:T	donor_loss	1.0000
6:46246746:A:AG	donor_loss	1.0000
6:46246920:C:CG	acceptor_loss	1.0000
6:46246924:CAAA:C	acceptor_gain	1.0000
6:46246927:A:AC	acceptor_gain	1.0000
6:46246927:A:C	acceptor_gain	1.0000
6:46248718:CTTA:C	donor_loss	1.0000
6:46248719:TTAC:T	donor_loss	1.0000
6:46248721:A:T	donor_loss	1.0000
6:46248722:C:A	donor_loss	1.0000
6:46248894:TTCC:T	acceptor_loss	1.0000
6:46248895:TCC:T	acceptor_loss	1.0000
6:46248896:CCT:C	acceptor_loss	1.0000
6:46248897:CTGAT:C	acceptor_loss	1.0000
6:46248898:T:C	acceptor_loss	1.0000
6:46248900:A:C	acceptor_gain	1.0000
6:46223297:CTCTC:C	acceptor_gain	0.9900
6:46223299:CTC:C	acceptor_gain	0.9900
6:46223300:TC:T	acceptor_gain	0.9900
6:46223300:TCC:T	acceptor_loss	0.9900
6:46223301:CC:C	acceptor_gain	0.9900
6:46223302:C:CA	acceptor_loss	0.9900
6:46223303:T:C	acceptor_loss	0.9900
6:46233105:T:TA	donor_gain	0.9900
6:46246746:A:AC	donor_gain	0.9900
6:46246747:C:CC	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003262 (6:46449661 T>C), RS1000009028 (6:46237898 T>C), RS1000009106 (6:46405992 C>G,T), RS1000013960 (6:46422462 G>A), RS1000029785 (6:46466581 A>G), RS1000045415 (6:46294396 T>C), RS1000058360 (6:46362711 G>A), RS1000070708 (6:46285794 C>T), RS1000084270 (6:46281122 G>A), RS1000094860 (6:46325392 C>T), RS1000102026 (6:46238144 T>C,G), RS1000108477 (6:46456009 C>T), RS1000124022 (6:46482147 G>T), RS1000132740 (6:46385327 C>T), RS1000138784 (6:46306893 A>G)

Disease associations

OMIM: gene MIM:604876 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002783_239	Body mass index	7.000000e-06
GCST010320_121	PR interval	1.000000e-14
GCST010321_24	PR interval	1.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004462	PR interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
trimellitic anhydride	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	affects methylation	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	increases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amphotericin B	decreases expression	1
Bleomycin	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1

Clinical trials (associated diseases)

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