RCAN1

Summary

RCAN1 (regulator of calcineurin 1, HGNC:3040) is a protein-coding gene on chromosome 21q22.12, encoding Calcipressin-1 (P53805). Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A.

The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways, possibly affecting central nervous system development. This gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of this gene may lead to neurofibrillary tangles such as those associated with Alzheimer disease. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1827 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal segmental glomerulosclerosis (Moderate, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 23 total
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3040
Approved symbol	RCAN1
Name	regulator of calcineurin 1
Location	21q22.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159200
Ensembl biotype	protein_coding
OMIM	602917
Entrez	1827

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000313806, ENST00000381132, ENST00000381135, ENST00000399272, ENST00000443408, ENST00000463276, ENST00000481448, ENST00000482533, ENST00000487434, ENST00000487990, ENST00000489903, ENST00000492600, ENST00000609325, ENST00000620920

RefSeq mRNA: 8 — MANE Select: NM_004414 NM_001285389, NM_001285391, NM_001285392, NM_001285393, NM_001331016, NM_004414, NM_203417, NM_203418

CCDS: CCDS13637, CCDS33551, CCDS42921, CCDS74788, CCDS74790, CCDS82668

Canonical transcript exons

ENST00000313806 — 4 exons

Exon	Start	End
ENSE00001869771	34614760	34615113
ENSE00003659681	34521499	34521658
ENSE00003708710	34523537	34523710
ENSE00003844069	34516442	34518256

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.8183 / max 1952.2195, expressed in 1790 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190286	24.5362	1346
190287	4.0532	1356
190291	1.7520	1060
190288	1.2948	527
190290	1.2296	682
209303	0.8398	536
190289	0.3935	205
190285	0.2155	73
190292	0.1530	38
190283	0.1490	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.81	gold quality
cranial nerve II	UBERON:0000941	98.59	gold quality
cartilage tissue	UBERON:0002418	98.55	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.82	gold quality
vena cava	UBERON:0004087	97.81	gold quality
epithelium of mammary gland	UBERON:0003244	97.59	gold quality
mammary duct	UBERON:0001765	97.58	gold quality
medial globus pallidus	UBERON:0002477	97.53	gold quality
spinal cord	UBERON:0002240	97.51	gold quality
renal glomerulus	UBERON:0000074	97.18	gold quality
metanephric glomerulus	UBERON:0004736	97.14	gold quality
mucosa of urinary bladder	UBERON:0001259	97.06	gold quality
left ventricle myocardium	UBERON:0006566	97.00	gold quality
globus pallidus	UBERON:0001875	96.94	gold quality
jejunal mucosa	UBERON:0000399	96.80	gold quality
kidney epithelium	UBERON:0004819	96.69	gold quality
secondary oocyte	CL:0000655	96.68	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.68	gold quality
stromal cell of endometrium	CL:0002255	96.40	gold quality
right lobe of liver	UBERON:0001114	96.36	gold quality
colonic mucosa	UBERON:0000317	96.26	gold quality
nephron tubule	UBERON:0001231	96.25	gold quality
putamen	UBERON:0001874	96.18	gold quality
substantia nigra	UBERON:0002038	96.15	gold quality
liver	UBERON:0002107	96.06	gold quality
inferior vagus X ganglion	UBERON:0005363	95.94	gold quality
midbrain	UBERON:0001891	95.90	gold quality
oocyte	CL:0000023	95.80	gold quality
olfactory bulb	UBERON:0002264	95.80	gold quality
hypothalamus	UBERON:0001898	95.71	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	1514.39
E-MTAB-10855	yes	1242.47
E-MTAB-10885	yes	433.40
E-MTAB-7008	yes	258.99
E-HCAD-11	yes	25.59
E-MTAB-10137	no	2517.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, ATP2B4, CEBPB, EGR1, FOXP1, GATA2, HES1, HESX1, HNF4A, JUN, NFATC1, NFATC2, NFATC4, STAT2

miRNA regulators (miRDB)

79 targeting RCAN1, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• RCAN1 interacts with the catalytic subunit (calcineurin A) of the phosphatase calcineurin (PMID:10861295)
• The involvement of amino acid residues that are prone to phosphorylation suggests that the location and function of DSCR1 may be regulated by kinases and/or phosphatases. (PMID:12225619)
• The RCAN1 protein isoforms are phosphorylated proteins (PMID:12809556)
• The negative regulatory feedback loop between DSCR1 and CnA signaling may represent a potential molecular mechanism underlying the frequently transient expression of inflammatory genes following activation of endothelial cells. (PMID:15016650)
• endogenous Adapt78 protein, like its mRNA, is oxidative and calcium stress responsive (PMID:15256217)
• DSCR1 is involved in angiogenesis by regulating adhesion and migration of endothelial cells via interaction with integrin alphavbeta3. (PMID:15263820)
• Results show that Down syndrome critical region 1 (DSCR1) is greatly induced in endothelial cells in response to VEGF (PMID:15358155)
• VEGF- and thrombin-mediated induction of endothelial cell proliferation triggers a negative feedback loop including DSCR-1 (PMID:15448146)
• Adapt 78 plays a role in basic T-cell response (PMID:16109302)
• Review concludes that this endogenous calcineurin inhibitor, calcipressin 1, may also play a role in a variety of human diseases, including Alzheimer’s disease, Down syndrome and cardiac hypertrophy. (PMID:16231093)
• Data show that the ELHA motif-containing calcineurin-inhibitor CALP1 motif is the responsible for the in vivo inhibition of calcineurin-mediated NFAT-dependent cytokine gene expression in human T cells. (PMID:16406492)
• review of roles of ITSN1 and DSCR1 in Down syndrome, Alzheimer’s disease, endocytosis and vesicle trafficking (PMID:16442855)
• DSCR-1 and I-kappaB may lend themselves to therapeutic manipulation in vasculopathic disease states. (PMID:16627481)
• There is now compelling evidence that the protein products of two genes on chromosome 21, Down syndrome candidate region 1 (DSCR1) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), interact functionally (PMID:16919501)
• DSCR1 attenuates NF-kappaB-mediated transcriptional activation by stabilizing its inhibitory protein, IkappaBalpha (PMID:17062574)
• DSCR1-1L, regulated by a different promoter than DSCR1-4, activates NFAT and its proangiogenic activity is inhibited by cyclosporin. (PMID:17114339)
• Isoprotein RCAN1-1 may play a role in Alzheimer’s disease, whereas isoprotein RCAN1-4 may serve another purpose. (PMID:17331188)
• analysis of the link between PPARgamma and calcium signaling and description of the role of DSCR1 in transformation of epithelial cells (PMID:17565986)
• These findings indicate that, although the up-regulation of DSCR1 levels exerts a cytotoxic effect, the addition of zinc leads to the formation of cytoprotective nuclear aggregates in neuronal cells. (PMID:17596961)
• DSCR1-L1 is constitutively expressed in endothelial cells and acts similar to DSCR1 in inhibiting calcineurin activity and restraining VEGF-mediated angiogenesis. (PMID:17610901)
• DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the endocardium during a critical window of heart valve formation. (PMID:17693409)
• These studies extend and complement previous studies on RCAN isoforms toward better understanding the role of RCAN1 in brain function and as a potential new target for treating calcineurin-related brain disorders. (PMID:17910944)
• NF-kappaB-inducing kinase phosphorylates and blocks the degradation of Down syndrome candidate region 1 (PMID:18056702)
• Rcan1 regulates the number of vesicles undergoing exocytosis and the speed at which the vesicle fusion pore opens and closes. (PMID:18180251)
• Our results reveal a newly identified vascular role for RCAN1, and a potential new target for treating vascular- and calcineurin-related disorders. (PMID:18294449)
• Damaging exercise induced the expression of capZalpha, MCIP1, CARP1, DNAJB2, c-myc, and junD, each of which are likely involved in skeletal muscle growth, remodeling, and stress management. (PMID:18321953)
• CREB decreases the protein level of RCAN1, which is overexpressed in the brain of Down Syndrome patients. (PMID:18485898)
• These results suggest that hydrogen peroxide induces SCF beta-TrCP-mediated ubiquitination of RCAN1, leading to a decrease in the protein level of RCAN1. (PMID:18575781)
• TEF3 mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells (PMID:18840614)
• increased phosphorylation of huntingtin via calcineurin inhibition, rather than via Akt induction or activation, is the likely mechanism by which RCAN1-1L may be protective against mutant huntingtin. (PMID:19270310)
• Regulator of calcineurin 1 modulates cancer cell migration in vitro. (PMID:19306109)
• Genes such as DSCR1 that are duplicated in Down syndrome might not play an important role in tumorigenesis of epithelial ovarian cancer. (PMID:19331211)
• Two distinct protein motifs in the C-terminal domain of RCAN1 are involved in binding to calcineurin and calcineurin inhibition (PMID:19332797)
• DSCR1 is increased in Down’s syndrome tissues (PMID:19458618)
• the molecular mechanism of RCAN1 protein degradation was investigated. (PMID:19509306)
• Results describe a novel role of RCAN1 isoform 4 in proper expression of Ras protein and its signaling. (PMID:19619541)
• DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation. (PMID:19716405)
• the accumulation of the RCAN1 protein by cAMP acts as an important regulatory mechanism in the control of the calcineurin-dependent cellular pathway. (PMID:19755121)
• 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)
• DSCR1 overexpression attenuates NFAT transcriptional activity in vascular smooth muscle cells. (PMID:19926569)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rcan1a	ENSDARG00000003109
		ENSDARG00000099004
mus_musculus	Rcan1	ENSMUSG00000022951
rattus_norvegicus	Rcan1	ENSRNOG00000001979
drosophila_melanogaster	sra	FBGN0086370
caenorhabditis_elegans		WBGENE00004321

Paralogs (2): RCAN3 (ENSG00000117602), RCAN2 (ENSG00000172348)

Protein

Protein identifiers

Calcipressin-1 — P53805 (reviewed: P53805)

Alternative names: Adapt78, Down syndrome critical region protein 1, Myocyte-enriched calcineurin-interacting protein 1, Regulator of calcineurin 1

All UniProt accessions (5): E9PD55, E9PDJ2, P53805, Q6FGP2, V9GYW9

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 RAF1. Interacts with PPP3CA and PPP3R1.

Tissue specificity. Highly expressed heart, brain and skeletal muscle. Also expressed in all other tissues.

Post-translational modifications. Phosphorylation increases its ability to inhibit calcineurin and decreases protein half-life.

Induction. By calcium.

Similarity. Belongs to the RCAN family.

Isoforms (4)

UniProt ID	Names	Canonical?
P53805-1	1, CALP1-L	yes
P53805-2	2, CALP1-S
P53805-3	3
P53805-4	4

RefSeq proteins (8): NP_001272318, NP_001272320, NP_001272321, NP_001272322, NP_001317945, NP_004405, NP_981962, NP_981963 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006931	Calcipressin	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034906	RCAN1_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF04847

UniProt features (16 total): mutagenesis site 4, modified residue 3, splice variant 3, sequence conflict 2, chain 1, region of interest 1, strand 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6UUQ	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53805-F1	75.31	0.34

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 (3): 163, 167, 218

Mutagenesis-validated functional residues (4):

Position	Phenotype
163	no loss of phosphorylation and no effect on protein half-life; alone or when associated with e-167.
167	loss of phosphorylation, no loss of interaction with ppp3ca and ppp3r1, reduced ability to inhibit calcineurin and incre
167	no loss of phosphorylation and no effect on protein half-life; alone or when associated with e-163.
163	loss of phosphorylation, no loss of interaction with ppp3ca and ppp3r1, reduced ability to inhibit calcineurin and incre

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 399 (showing top): ATF_B, GOBP_MEMORY, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, PEREZ_TP63_TARGETS, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (13): response to ischemia (GO:0002931), response to oxidative stress (GO:0006979), short-term memory (GO:0007614), response to mechanical stimulus (GO:0009612), calcium-mediated signaling (GO:0019722), locomotion involved in locomotory behavior (GO:0031987), calcineurin-NFAT signaling cascade (GO:0033173), response to estrogen (GO:0043627), skeletal muscle fiber development (GO:0048741), negative regulation of smooth muscle cell differentiation (GO:0051151), negative regulation of calcineurin-NFAT signaling cascade (GO:0070885), response to stress (GO:0006950), skeletal muscle tissue development (GO:0007519)

GO Molecular Function (5): nucleic acid binding (GO:0003676), protein phosphatase inhibitor activity (GO:0004864), calcium-dependent protein serine/threonine phosphatase regulator activity (GO:0008597), identical protein binding (GO:0042802), protein binding (GO:0005515)

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	2
binding	2
protein phosphatase regulator activity	2
memory	1
response to external stimulus	1
response to abiotic stimulus	1
intracellular signaling cassette	1
locomotory behavior	1
locomotion	1
calcineurin-mediated signaling	1
response to hormone	1
skeletal muscle tissue development	1
myotube cell development	1
smooth muscle cell differentiation	1
negative regulation of muscle cell differentiation	1
regulation of smooth muscle cell differentiation	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
negative regulation of calcineurin-mediated signaling	1
response to stimulus	1
striated muscle tissue development	1
skeletal muscle organ development	1
phosphoprotein phosphatase activity	1
phosphatase inhibitor activity	1
calcium-dependent protein serine/threonine phosphatase activity	1
protein binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1130 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RCAN1	DYRK1A	Q13627	874
RCAN1	NFATC1	O95644	789
RCAN1	PPP3CA	Q08209	761
RCAN1	NFATC2	Q13469	729
RCAN1	CALML3	P27482	725
RCAN1	CALML5	Q9NZT1	725
RCAN1	CALML6	Q8TD86	710
RCAN1	CALML4	Q96GE6	710
RCAN1	CALM1	P02593	709
RCAN1	SYNJ1	O43426	668
RCAN1	CABIN1	Q9Y6J0	645
RCAN1	AKAP5	P24588	610
RCAN1	MYOZ2	Q9NPC6	604
RCAN1	GSK3B	P49841	594
RCAN1	PSMG1	O95456	585

IntAct

39 interactions, top by confidence:

A	B	Type	Score
PABIR1	PPP2R1A	psi-mi:“MI:0914”(association)	0.880
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RCAN1	PPP3CB	psi-mi:“MI:0914”(association)	0.660
SRBD1	PPP3CC	psi-mi:“MI:0914”(association)	0.530
PPP3CC	GSK3A	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
RCAN1	PRKACB	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CATSPER2	RCAN1	psi-mi:“MI:0915”(physical association)	0.400
RCAN1		psi-mi:“MI:0915”(physical association)	0.370
PPP3CA	RCAN1	psi-mi:“MI:0914”(association)	0.350
PPP3CB	PI4KA	psi-mi:“MI:0914”(association)	0.350
PPP3CC	PI4KA	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CALM2	MYO1C	psi-mi:“MI:0914”(association)	0.350
CALM3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PPP3R2	ANKRD33B	psi-mi:“MI:0914”(association)	0.350
RCAN1	CLEC3A	psi-mi:“MI:0914”(association)	0.350
PPP3R2	MAP2K7	psi-mi:“MI:0914”(association)	0.350
NRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
LARP7	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
ZC3H11A	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
RCAN1	SPARCL1	psi-mi:“MI:0915”(physical association)	0.000
RCAN1	PICK1	psi-mi:“MI:0915”(physical association)	0.000
RCAN1	SF3A2	psi-mi:“MI:0915”(physical association)	0.000
RCAN1	PRDM4	psi-mi:“MI:0915”(physical association)	0.000
RCAN1	ZNF350	psi-mi:“MI:0915”(physical association)	0.000
RCAN1	PTPRD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (82): RCAN1 (Affinity Capture-MS), RCAN1 (Affinity Capture-MS), RCAN1 (Affinity Capture-MS), USP22 (Affinity Capture-Western), RCAN1 (Affinity Capture-Western), USP22 (Two-hybrid), RCAN1 (Affinity Capture-MS), RCAN1 (Affinity Capture-MS), RCAN1 (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), GSK3A (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), C6orf211 (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

15 interactions.

A	Effect	B	Mechanism
DYRK1A	up-regulates	RCAN1	phosphorylation
MAP3K3	up-regulates	RCAN1	phosphorylation
RCAN1	“down-regulates activity”	PPP3CA	binding
RCAN1	“down-regulates activity”	Calcineurin	binding
LRRK2	“up-regulates activity”	RCAN1	phosphorylation
MAP3K7	“up-regulates activity”	RCAN1	phosphorylation
MAPK1	“up-regulates activity”	RCAN1	phosphorylation
GSK3B	“up-regulates activity”	RCAN1	phosphorylation
MAPK3	“up-regulates activity”	RCAN1	phosphorylation
HES1	“down-regulates quantity by repression”	RCAN1	“transcriptional regulation”
JUN	“up-regulates quantity by expression”	RCAN1	“transcriptional regulation”
Gbeta	“up-regulates activity”	RCAN1	phosphorylation
ERK1/2	“up-regulates activity”	RCAN1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DARPP-32 events	6	89.2×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of calcineurin-NFAT signaling cascade	5	95.5×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

319 predictions. Top by Δscore:

Variant	Effect	Δscore
21:34518255:CC:C	acceptor_gain	1.0000
21:34518256:CC:C	acceptor_gain	1.0000
21:34518257:C:CC	acceptor_gain	1.0000
21:34518258:T:C	acceptor_loss	1.0000
21:34521494:CTCA:C	donor_loss	1.0000
21:34521495:TCA:T	donor_loss	1.0000
21:34521496:CA:C	donor_loss	1.0000
21:34521497:ACCT:A	donor_loss	1.0000
21:34521498:C:CG	donor_loss	1.0000
21:34521655:AGGT:A	acceptor_gain	1.0000
21:34521657:GTC:G	acceptor_loss	1.0000
21:34521659:C:CA	acceptor_loss	1.0000
21:34523532:CTCA:C	donor_loss	1.0000
21:34523534:CA:C	donor_loss	1.0000
21:34523535:A:AC	donor_gain	1.0000
21:34523536:C:CC	donor_gain	1.0000
21:34523536:C:G	donor_loss	1.0000
21:34523711:C:CC	acceptor_gain	1.0000
21:34518252:TTCCC:T	acceptor_gain	0.9900
21:34518253:TCCC:T	acceptor_gain	0.9900
21:34518254:CCC:C	acceptor_gain	0.9900
21:34518254:CCCC:C	acceptor_gain	0.9900
21:34518255:CCC:C	acceptor_gain	0.9900
21:34518257:C:T	acceptor_gain	0.9900
21:34521493:GCTCA:G	donor_loss	0.9900
21:34521497:A:AC	donor_gain	0.9900
21:34521498:C:CC	donor_gain	0.9900
21:34521498:CCTGG:C	donor_gain	0.9900
21:34521654:AAGGT:A	acceptor_gain	0.9900
21:34521656:GGT:G	acceptor_gain	0.9900

AlphaMissense

1657 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:34518205:A:T	V213D	1.000
21:34521528:A:G	L186P	1.000
21:34521569:C:A	W172C	1.000
21:34521569:C:G	W172C	1.000
21:34521571:A:G	W172R	1.000
21:34521571:A:T	W172R	1.000
21:34521605:A:C	F160L	1.000
21:34521605:A:T	F160L	1.000
21:34521607:A:G	F160L	1.000
21:34523637:A:T	V109D	1.000
21:34518211:A:T	V211E	0.999
21:34518217:G:T	P209H	0.999
21:34518241:A:G	L201S	0.999
21:34521570:C:A	W172L	0.999
21:34521570:C:G	W172S	0.999
21:34521600:A:T	I162N	0.999
21:34521603:A:G	L161P	0.999
21:34521624:G:T	P154Q	0.999
21:34521633:A:G	L151P	0.999
21:34523541:G:T	A141D	0.999
21:34523586:A:G	L126P	0.999
21:34523598:G:T	A122D	0.999
21:34523625:A:G	F113S	0.999
21:34523631:A:T	I111K	0.999
21:34523640:C:G	R108P	0.999
21:34523645:G:C	F106L	0.999
21:34523645:G:T	F106L	0.999
21:34523646:A:G	F106S	0.999
21:34523647:A:G	F106L	0.999
21:34523648:G:C	S105R	0.999

dbSNP variants (sampled 300 via entrez): RS1000003308 (21:34540200 T>C), RS1000051504 (21:34574048 G>C,T), RS1000079514 (21:34535303 C>T), RS1000105964 (21:34605362 C>T), RS1000112507 (21:34599605 C>G), RS1000157220 (21:34602299 G>A), RS1000158927 (21:34608525 A>G), RS1000203605 (21:34557206 C>G), RS1000211636 (21:34608874 G>C), RS1000222824 (21:34530170 C>T), RS1000302070 (21:34596568 G>A), RS1000334577 (21:34523906 C>T), RS1000342036 (21:34562267 G>A,C), RS1000373079 (21:34562496 G>C,T), RS1000389345 (21:34517936 C>G,T)

Disease associations

OMIM: gene MIM:602917 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
focal segmental glomerulosclerosis	Moderate	Autosomal dominant

Mondo (1): focal segmental glomerulosclerosis (MONDO:0100313)

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002318_100	Rheumatoid arthritis	7.000000e-07
GCST002318_30	Rheumatoid arthritis	3.000000e-07
GCST005275_1	Cancer	5.000000e-07
GCST005568_4	Rheumatoid arthritis (ACPA-positive)	3.000000e-08
GCST005569_26	Rheumatoid arthritis	4.000000e-07
GCST006048_23	Rheumatoid arthritis (ACPA-positive)	4.000000e-06
GCST006959_119	Rheumatoid arthritis	7.000000e-07
GCST006959_71	Rheumatoid arthritis	3.000000e-07

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Benzo(a)pyrene	affects methylation, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases expression, decreases expression, increases abundance	3
bisphenol A	decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	decreases expression, increases abundance, increases expression	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Estradiol	affects binding, increases expression	2
Lead	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
Zinc	affects cotreatment, increases expression, decreases response to substance	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases methylation, increases expression	2
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
geraniol	increases expression	1
sodium arsenate	increases abundance, decreases expression	1
arsenite	affects binding, decreases reaction	1
nickel chloride	increases expression	1
oxophenylarsine	decreases reaction, increases phosphorylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
15-acetyldeoxynivalenol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TI64	HAP1 RCAN1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT01164098	PHASE3	TERMINATED	Rituximab to Prevent Recurrence of Proteinuria
NCT02683889	PHASE3	COMPLETED	Use of Acthar in Patients With FSGS That Will be Undergoing Renal Transplantation
NCT03298698	PHASE3	UNKNOWN	Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
NCT03493685	PHASE3	COMPLETED	Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)
NCT05183646	PHASE3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB
NCT07220083	PHASE3	RECRUITING	A Study to Find Out if BI 764198 Helps Adults and Adolescents With a Kidney Condition Called Focal Segmental Glomerulosclerosis (FSGS)
NCT00550342	PHASE2	WITHDRAWN	Rituximab Treatment of Focal Segmental Glomerulosclerosis
NCT00814255	PHASE2	COMPLETED	Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial
NCT01613118	PHASE2	COMPLETED	Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT03366337	PHASE2	COMPLETED	A Phase 2 Trial of the Safety and Efficacy of Bardoxolone Methyl in Patients With Rare Chronic Kidney Diseases - PHOENIX
NCT03448692	PHASE2	TERMINATED	A Study to Evaluate PF-06730512 in Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT03536754	PHASE2	COMPLETED	A Study of CCX140-B in Subjects With FSGS
NCT03598036	PHASE2	TERMINATED	Dose-Exploration Evaluating the Efficacy and Safety of Voclosporin in Subjects With Focal Segmental Glomerulosclerosis
NCT03649152	PHASE2	COMPLETED	Safety and Effectiveness of Propagermanium in Focal Segmental Glomerulosclerosis Participants Receiving Irbesartan
NCT03703908	PHASE2	TERMINATED	A Study of CCX140-B in Subjects With Primary FSGS and Nephrotic Syndrome
NCT04009668	PHASE2	COMPLETED	Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease
NCT04573920	PHASE2	ACTIVE_NOT_RECRUITING	Atrasentan in Patients With Proteinuric Glomerular Diseases
NCT05003986	PHASE2	RECRUITING	Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases
NCT05267262	PHASE2	COMPLETED	Study to Evaluate R3R01 in Patients With Alport Syndrome and Patients With Focal Segmental Glomerulosclerosis
NCT05441826	PHASE2	TERMINATED	Efficacy and Safety of VB119 in Subjects With Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS)
NCT06500702	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of Frexalimab, Brivekimig, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease
NCT06664814	PHASE2	RECRUITING	An Open-Label Phase 2 Study of N-Acetyl-D-Mannosamine (ManNAc) in Subjects With Primary Focal Segmental Glomerulosclerosis
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases
NCT07268638	PHASE2	RECRUITING	A Study of Praliciguat in Participants With Focal Segmental Glomerulosclerosis (FSGS)
NCT07614477	PHASE2	RECRUITING	Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of EVER001 in Participants With Selected Proteinuric Glomerular Diseases
NCT00464321	PHASE1	COMPLETED	Safety Study of GC1008 in Patients With Focal Segmental Glomerulosclerosis (FSGS) of Single Doses of GC1008 in Patients With Treatment Resistant Idiopathic FSGS
NCT00782561	PHASE1	TERMINATED	Safety and Pharmacokinetics of FG-3019 in Adolescents and Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT00816478	PHASE1	TERMINATED	Effect of Oral Galactose on Focal Segmental Glomerulosclerosis (FSGS) Permeability Factor
NCT00816504	PHASE1	WITHDRAWN	Effect of Galactose on Permeblity Factor in Patients With FSGS and CKD Stage 5
NCT02382874	PHASE1	UNKNOWN	Allogenic AD-MSC Transplantation in Idiopathic Nephrotic Syndrome (Focal Segmental Glomerulosclerosis)
NCT02693366	PHASE1	COMPLETED	Stem Cell Therapy for Patients With Focal Segmental Glomerulosclerosis
NCT05942625	PHASE1	RECRUITING	A First in Human Study to Evaluate Safety, Tolerability, Pharmacology of HS-10390 in Healthy Subjects
NCT05955872	PHASE1	COMPLETED	A Study Evaluating the Relative Bioavailability and Food Effect of a Tablet Formulation of VX-147
NCT06529796	PHASE1	COMPLETED	Evaluation of the Pharmacokinetics and Safety of Inaxaplin in Participants With Mild or Moderate Hepatic Impairment