RCAN3

Summary

RCAN3 (regulator of calcineurin 3, HGNC:3042) is a protein-coding gene on chromosome 1p36.11, encoding Calcipressin-3 (Q9UKA8). Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A.

Enables phosphatase binding activity and troponin I binding activity. Predicted to be involved in calcium-mediated signaling. Predicted to be located in cytosol. Predicted to be active in cytoplasm and nucleus.

Source: NCBI Gene 11123 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_013441

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3042
Approved symbol	RCAN3
Name	regulator of calcineurin 3
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000117602
Ensembl biotype	protein_coding
OMIM	605860
Entrez	11123

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 nonsense_mediated_decay

ENST00000374393, ENST00000374395, ENST00000412742, ENST00000425530, ENST00000482807, ENST00000538532, ENST00000616511, ENST00000618490, ENST00000630217, ENST00000938486, ENST00000938487, ENST00000938488, ENST00000938489

RefSeq mRNA: 10 — MANE Select: NM_013441 NM_001251977, NM_001251978, NM_001251979, NM_001251980, NM_001251981, NM_001251982, NM_001251983, NM_001251984, NM_001251985, NM_013441

CCDS: CCDS254, CCDS57979, CCDS57980, CCDS57981, CCDS57982, CCDS72730

Canonical transcript exons

ENST00000374395 — 5 exons

Exon	Start	End
ENSE00000759681	24531218	24531391
ENSE00000759682	24533083	24533254
ENSE00001819041	24535093	24541040
ENSE00003569573	24514314	24514567
ENSE00003845564	24502836	24503150

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.7613 / max 642.0673, expressed in 1651 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1404	7.6563	1485
1398	4.2718	803
1403	3.7179	1135
1402	1.7173	708
1399	0.6743	164
1401	0.5313	237
1400	0.1026	46
1405	0.0900	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	98.12	gold quality
epithelium of nasopharynx	UBERON:0001951	94.61	gold quality
sperm	CL:0000019	94.37	gold quality
esophagus squamous epithelium	UBERON:0006920	94.12	gold quality
upper leg skin	UBERON:0004262	93.71	gold quality
cerebellar vermis	UBERON:0004720	93.71	gold quality
gingival epithelium	UBERON:0001949	93.57	gold quality
gingiva	UBERON:0001828	93.17	gold quality
corpus epididymis	UBERON:0004359	92.67	gold quality
skin of hip	UBERON:0001554	92.61	gold quality
parotid gland	UBERON:0001831	92.04	gold quality
oral cavity	UBERON:0000167	91.54	gold quality
male germ cell	CL:0000015	90.53	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.11	gold quality
islet of Langerhans	UBERON:0000006	89.60	gold quality
caput epididymis	UBERON:0004358	89.46	gold quality
palpebral conjunctiva	UBERON:0001812	88.88	gold quality
tonsil	UBERON:0002372	88.88	gold quality
epithelium of bronchus	UBERON:0002031	88.47	gold quality
mammary duct	UBERON:0001765	88.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.30	gold quality
bronchus	UBERON:0002185	88.23	gold quality
cerebellar cortex	UBERON:0002129	87.59	gold quality
mammalian vulva	UBERON:0000997	87.46	gold quality
cerebellar hemisphere	UBERON:0002245	87.44	gold quality
cerebellum	UBERON:0002037	87.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.22	gold quality
epithelium of esophagus	UBERON:0001976	86.78	gold quality
tibia	UBERON:0000979	86.10	gold quality
secondary oocyte	CL:0000655	85.61	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.52
E-MTAB-6379	no	3410.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SLC8A2

miRNA regulators (miRDB)

76 targeting RCAN3, 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-4455	100.00	65.48	1587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4694-3P	99.79	69.53	2640

Literature-anchored findings (GeneRIF, showing 10)

• The yeast cotransformation and GST fusion protein assay demonstrated the interaction between this new DSCR1L2 variant and the human cardiac troponin I. (PMID:16516408)
• human RCAN3, encoded by the RCAN3 (also known as DSCR1L2) gene, interacts physically and functionally with calcineurin (PMID:17270291)
• The interaction between TNNI3 and the new R variants of RCAN3, RCAN3-2,3,5 and RCAN3-2,4,5, is reported. (PMID:18022329)
• 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)
• Data shows RCAN3 inhibits HUVEC proliferation both basally and under VEGF or phorbol 12-myristate 13-acetate-stimulated conditions, however it does not modulate gene expression of the chosen inflammatory genes. (PMID:21042787)
• Studies indicate that RCAN3 is composed of a multigene system that includes at least 21 alternative spliced isoforms. (PMID:21961037)
• The tumor suppressor effect of RCAN3 in breast cancer depends on the interaction with calcineurin. (PMID:25916653)
• Functional implications of miR-145/RCAN3 axis in the progression of cervical cancer. (PMID:32345470)
• The PxIxIT motif of the RCAN3 inhibits angiogenesis and tumor progression in Triple Negative breast cancer in immunocompetent mice. (PMID:35640493)
• RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium. (PMID:38181896)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rcan3	ENSDARG00000032623
mus_musculus	Rcan3	ENSMUSG00000059713
rattus_norvegicus	Rcan3	ENSRNOG00000018576
drosophila_melanogaster	sra	FBGN0086370
caenorhabditis_elegans		WBGENE00004321

Paralogs (2): RCAN1 (ENSG00000159200), RCAN2 (ENSG00000172348)

Protein

Protein identifiers

Calcipressin-3 — Q9UKA8 (reviewed: Q9UKA8)

Alternative names: Down syndrome candidate region 1-like protein 2, Myocyte-enriched calcineurin-interacting protein 3, Regulator of calcineurin 3

All UniProt accessions (2): Q9UKA8, H0YF64

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.

Subunit / interactions. Interacts with protein phosphatase PPP3CA/calcineurin A.

Tissue specificity. Highest expression in heart, skeletal muscle kidney, liver and peripheral blood leukocytes. Lower expression in all other tissues.

Similarity. Belongs to the RCAN family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9UKA8-1	1, RCAN3-1a,2,3,4,5	yes
Q9UKA8-2	2
Q9UKA8-3	3
Q9UKA8-4	4
Q9UKA8-5	5, RCAN3-2,4,5, RCAN3-1c,2,4,5
Q9UKA8-6	6, RCAN3-1,3,4,5, RCAN3-1a,3,4,5, RCAN3-1c,3,4,5

RefSeq proteins (10): NP_001238906, NP_001238907, NP_001238908, NP_001238909, NP_001238910, NP_001238911, NP_001238912, NP_001238913, NP_001238914, NP_038469* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF04847

UniProt features (15 total): splice variant 7, region of interest 3, sequence conflict 2, chain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKA8-F1	74.41	0.36

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses

MSigDB gene sets: 182 (showing top): GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, SABATES_COLORECTAL_ADENOMA_SIZE_DN, LIAO_METASTASIS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, NUYTTEN_NIPP1_TARGETS_DN, GOMF_PHOSPHATASE_BINDING, GOMF_CYTOSKELETAL_PROTEIN_BINDING, GOMF_ENZYME_REGULATOR_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_PHOSPHATASE_REGULATOR_ACTIVITY, chr1p36, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, WONG_ADULT_TISSUE_STEM_MODULE

GO Biological Process (2): anatomical structure morphogenesis (GO:0009653), calcium-mediated signaling (GO:0019722)

GO Molecular Function (6): RNA binding (GO:0003723), calcium-dependent protein serine/threonine phosphatase regulator activity (GO:0008597), phosphatase binding (GO:0019902), troponin I binding (GO:0031013), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SARS-CoV-1-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
developmental process	1
anatomical structure development	1
intracellular signaling cassette	1
nucleic acid binding	1
calcium-dependent protein serine/threonine phosphatase activity	1
protein phosphatase regulator activity	1
enzyme binding	1
cytoskeletal protein binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RCAN3	PPP3CB	P16298	693
RCAN3	TNNI3	P19429	655
RCAN3	NFATC1	O95644	612
RCAN3	PPP3CA	Q08209	566
RCAN3	DAZAP1	Q96EP5	543
RCAN3	SIK2	Q9H0K1	495
RCAN3	NPPB	P16860	495
RCAN3	F2R	P25116	490
RCAN3	DYRK1A	Q13627	462
RCAN3	GON4L	Q3T8J9	458
RCAN3	MAPKBP1	O60336	440
RCAN3	GATA2	P23769	435
RCAN3	RSPH3	Q86UC2	429
RCAN3	PTTG2	Q9NZH5	429
RCAN3	DEGS2	Q6QHC5	425

IntAct

40 interactions, top by confidence:

A	B	Type	Score
RCAN3	GRB10	psi-mi:“MI:0915”(physical association)	0.570
GRB10	RCAN3	psi-mi:“MI:0915”(physical association)	0.570
TRIM23	RCAN3	psi-mi:“MI:0915”(physical association)	0.560
UNC119	RCAN3	psi-mi:“MI:0915”(physical association)	0.560
HTT	RCAN3	psi-mi:“MI:0915”(physical association)	0.560
PPP3CC	GSK3A	psi-mi:“MI:0914”(association)	0.530
RCAN3	rep	psi-mi:“MI:0915”(physical association)	0.510
EPS8	RCAN3	psi-mi:“MI:0915”(physical association)	0.370
RCAN3	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370
RCAN3	OBSL1	psi-mi:“MI:0914”(association)	0.350
PPP3CB	PI4KA	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): RCAN3 (Two-hybrid), PPP3CB (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), C6orf211 (Affinity Capture-MS), CDK4 (Affinity Capture-MS), OBSL1 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), SMYD3 (Affinity Capture-MS), RCAN3 (Two-hybrid), RCAN3 (Two-hybrid), GRB10 (Affinity Capture-Luminescence), RCAN3 (Affinity Capture-MS), RCAN3 (Affinity Capture-MS), PPP3CC (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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

694 predictions. Top by Δscore:

Variant	Effect	Δscore
1:24514312:AGTG:A	acceptor_gain	1.0000
1:24514313:GTGG:G	acceptor_gain	1.0000
1:24514564:GAAG:G	donor_gain	1.0000
1:24514567:GGT:G	donor_loss	1.0000
1:24514569:T:A	donor_loss	1.0000
1:24531371:C:G	donor_gain	1.0000
1:24531387:CACAG:C	donor_loss	1.0000
1:24531388:ACAG:A	donor_loss	1.0000
1:24531389:CAGGT:C	donor_loss	1.0000
1:24531390:AGGT:A	donor_loss	1.0000
1:24531391:GGTAC:G	donor_loss	1.0000
1:24531392:G:C	donor_loss	1.0000
1:24531393:T:A	donor_loss	1.0000
1:24535090:CA:C	acceptor_loss	1.0000
1:24535091:A:AG	acceptor_gain	1.0000
1:24535091:AG:A	acceptor_gain	1.0000
1:24535092:G:GT	acceptor_gain	1.0000
1:24535092:GG:G	acceptor_gain	1.0000
1:24535092:GGA:G	acceptor_gain	1.0000
1:24535092:GGAGA:G	acceptor_gain	1.0000
1:24514311:CAGT:C	acceptor_loss	0.9900
1:24514312:A:AG	acceptor_gain	0.9900
1:24514312:AGT:A	acceptor_gain	0.9900
1:24514313:G:GC	acceptor_gain	0.9900
1:24514313:GT:G	acceptor_gain	0.9900
1:24514313:GTG:G	acceptor_gain	0.9900
1:24514493:GATT:G	donor_gain	0.9900
1:24514568:G:GG	donor_gain	0.9900
1:24531194:T:TA	acceptor_gain	0.9900
1:24531202:T:A	acceptor_gain	0.9900

AlphaMissense

1608 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:24514524:C:A	A51D	0.999
1:24531289:A:C	R89S	0.999
1:24531289:A:T	R89S	0.999
1:24531291:T:A	V90D	0.999
1:24531333:G:C	R104P	0.999
1:24533146:T:C	F145L	0.999
1:24533148:C:A	F145L	0.999
1:24533148:C:G	F145L	0.999
1:24533182:T:A	W157R	0.999
1:24533182:T:C	W157R	0.999
1:24533184:G:C	W157C	0.999
1:24533184:G:T	W157C	0.999
1:24533237:T:A	V175D	0.999
1:24535144:T:A	V198D	0.999
1:24531281:T:C	F87L	0.998
1:24531283:T:A	F87L	0.998
1:24531283:T:G	F87L	0.998
1:24531297:T:A	I92K	0.998
1:24531330:C:A	A103E	0.998
1:24531342:T:C	L107P	0.998
1:24535108:T:A	L186H	0.998
1:24535108:T:C	L186P	0.998
1:24535138:T:A	V196E	0.998
1:24514533:T:A	V54D	0.997
1:24531237:T:C	F72S	0.997
1:24531288:G:C	R89T	0.997
1:24531297:T:G	I92R	0.997
1:24531303:T:C	F94S	0.997
1:24531321:C:A	A100E	0.997
1:24531329:G:C	A103P	0.997

dbSNP variants (sampled 300 via entrez): RS1000002780 (1:24511786 A>G), RS1000045990 (1:24508925 C>T), RS1000149341 (1:24515535 C>G), RS1000289074 (1:24521861 C>A,G,T), RS1000345478 (1:24528599 A>T), RS1000422240 (1:24528155 G>T), RS1000514106 (1:24513557 T>G), RS1000556130 (1:24504996 C>G,T), RS1000592465 (1:24520748 G>A,T), RS1000662193 (1:24522043 GT>G), RS1000684761 (1:24526755 C>T), RS1000764715 (1:24521563 T>C), RS1001009418 (1:24539684 AT>A), RS1001025108 (1:24520469 G>A), RS1001026532 (1:24527246 G>A,C)

Disease associations

OMIM: gene MIM:605860 | 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
GCST006661_182	Male-pattern baldness	1.000000e-10
GCST006661_57	Male-pattern baldness	4.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	4
methylmercuric chloride	decreases expression	3
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentabromodiphenyl ether	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Bortezomib	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1

Clinical trials (associated diseases)

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