RCVRN

Summary

RCVRN (recoverin, HGNC:9937) is a protein-coding gene on chromosome 17p13.1, encoding Recoverin (P35243). Acts as a calcium sensor and regulates phototransduction of cone and rod photoreceptor cells.

This gene encodes a member of the recoverin family of neuronal calcium sensors. The encoded protein contains three calcium-binding EF-hand domains and may prolong the termination of the phototransduction cascade in the retina by blocking the phosphorylation of photo-activated rhodopsin. Recoverin may be the antigen responsible for cancer-associated retinopathy.

Source: NCBI Gene 5957 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 23 total
• MANE Select transcript: NM_002903

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9937
Approved symbol	RCVRN
Name	recoverin
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109047
Ensembl biotype	protein_coding
OMIM	179618
Entrez	5957

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000226193, ENST00000570909

RefSeq mRNA: 1 — MANE Select: NM_002903 NM_002903

CCDS: CCDS11151

Canonical transcript exons

ENST00000226193 — 3 exons

Exon	Start	End
ENSE00000684918	9900989	9901100
ENSE00000855139	9904800	9905271
ENSE00001294803	9896320	9898204

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 78.13.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.6828 / max 2585.5624, expressed in 17 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164511	5.4592	14
164510	0.1072	8
164506	0.0495	6
164509	0.0299	5
164512	0.0142	5
164507	0.0115	4
164508	0.0113	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.13	gold quality
type B pancreatic cell	CL:0000169	73.33	gold quality
olfactory bulb	UBERON:0002264	73.30	gold quality
retina	UBERON:0000966	71.70	gold quality
pigmented layer of retina	UBERON:0001782	71.69	gold quality
pineal body	UBERON:0001905	68.17	silver quality
cortical plate	UBERON:0005343	68.03	gold quality
endometrium epithelium	UBERON:0004811	67.67	gold quality
right frontal lobe	UBERON:0002810	66.10	gold quality
cingulate cortex	UBERON:0003027	65.53	gold quality
anterior cingulate cortex	UBERON:0009835	65.22	gold quality
granulocyte	CL:0000094	65.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.67	gold quality
diaphragm	UBERON:0001103	63.03	gold quality
thymus	UBERON:0002370	62.89	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	62.45	gold quality
mononuclear cell	CL:0000842	61.52	gold quality
monocyte	CL:0000576	61.47	gold quality
leukocyte	CL:0000738	61.25	gold quality
neocortex	UBERON:0001950	61.19	gold quality
tongue squamous epithelium	UBERON:0006919	60.84	gold quality
frontal cortex	UBERON:0001870	60.71	gold quality
omental fat pad	UBERON:0010414	60.57	gold quality
peritoneum	UBERON:0002358	60.56	gold quality
left uterine tube	UBERON:0001303	60.34	gold quality
Brodmann (1909) area 46	UBERON:0006483	60.17	gold quality
cerebral cortex	UBERON:0000956	59.64	gold quality
adipose tissue of abdominal region	UBERON:0007808	59.51	gold quality
orbitofrontal cortex	UBERON:0004167	59.50	gold quality
vastus lateralis	UBERON:0001379	59.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	11662.95
E-MTAB-11121	yes	7666.83
E-GEOD-137537	yes	4478.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1D1, NR2E3, RBPJ

miRNA regulators (miRDB)

34 targeting RCVRN, 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-6867-5P	100.00	82.21	3464
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-27B-5P	97.34	66.55	549
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-28-5P	96.16	66.12	579

Literature-anchored findings (GeneRIF, showing 11)

• recoverin has a pathological role in cancer-associated retinopathy (PMID:12596918)
• There are cis-acting elements in the 5’ non-coding region of the recoverin gene that are involved in the activation and suppression of gene expression. (PMID:12789533)
• Human recoverin is expressed in SCLC cells cultured from an anti-recoverin antibody-negative patient with CAR. KK0206 might be important for further research on SCLC related retinopathy. (PMID:17374419)
• A GRK1 region close to its C-terminus also seemed to be the binding site for S-modulin/recoverin. (PMID:18266817)
• Aberrant hypomethylation of the recoverin gene region, overlapping the promoter up-stream of the first exon and the first exon itself, is involved in the aberrant expression of recoverin in tumor cells. (PMID:20812967)
• C39D substitution reduces alpha-helical content, decreases thermal stability and suppresses membrane association. (PMID:21344177)
• Crystal Structure of Recoverin with Calcium Ions Bound to Both Functional EF Hands. (PMID:26584024)
• High RCVRN expression is associated with renal tumors. (PMID:26813565)
• these data confirm the scaffolding function of several cluster-forming residues and point to their critical role in supporting physiological activity of recoverin (PMID:31288444)
• Recoverin (Rec) is a prototypical calcium sensor protein primarily expressed in the vertebrate retina. The binding of two Ca(2+) ions to the functional EF-hand motifs induces the extrusion of a myristoyl group that increases the affinity of Rec for the membrane and leads to the formation of a complex with rhodopsin kinase (GRK1). (PMID:31658639)
• Serum anti-recoverin antibodies is found in elderly patients with retinitis pigmentosa and cancer. (PMID:32043815)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	rcvrn3	ENSDARG00000009637
danio_rerio	rcvrn2	ENSDARG00000019902
mus_musculus	Rcvrn	ENSMUSG00000020907
rattus_norvegicus	Rcvrn	ENSRNOG00000003633
drosophila_melanogaster	CG7646	FBGN0036926
drosophila_melanogaster	CG5890	FBGN0039380
caenorhabditis_elegans	ncs-2	WBGENE00003564
caenorhabditis_elegans		WBGENE00015867

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCALD (ENSG00000104490), NCS1 (ENSG00000107130), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), HPCA (ENSG00000121905), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Recoverin — P35243 (reviewed: P35243)

Alternative names: Cancer-associated retinopathy protein

All UniProt accessions (1): P35243

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a calcium sensor and regulates phototransduction of cone and rod photoreceptor cells. Modulates light sensitivity of cone photoreceptor in dark and dim conditions. In response to high Ca(2+) levels induced by low light levels, prolongs RHO/rhodopsin activation in rod photoreceptor cells by binding to and inhibiting GRK1-mediated phosphorylation of RHO/rhodopsin. Plays a role in scotopic vision/enhances vision in dim light by enhancing signal transfer between rod photoreceptors and rod bipolar cells. Improves rod photoreceptor sensitivity in dim light and mediates response of rod photoreceptors to facilitate detection of change and motion in bright light.

Subunit / interactions. Homodimer; disulfide-linked. Homodimerization is caused by prolonged intense illumination. May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO. Interacts (via C-terminus) with GRK1 (via N-terminus); the interaction is Ca(2+)-dependent.

Subcellular location. Photoreceptor inner segment. Cell projection. Cilium. Photoreceptor outer segment. Photoreceptor outer segment membrane. Perikaryon.

Tissue specificity. Retina and pineal gland.

Post-translational modifications. The N-terminal glycine is linked to one of four different types of acyl groups. The most abundant is myristoleate (14:1), but 14:0, 14:2, and 12:0 acyl residues are also present. The Ca(2+) induced exposure of the myristoyl group, known as the calcium-myristoyl switch, promotes RCVRN binding to the photoreceptor cell membranes only when intracellular Ca(2+) concentration is high. Oxidation on Cys-39 occurs in response to prolonged intense illumination and results in the formation of disulfide homodimers, and to a lesser extent disulfide-linked heterodimers.

Domain organisation. EF-hand 2 and EF-hand 3 domains are the low-affinity and the high-affinity calcium binding sites, respectively. EF-hand 1 and EF-hand 4 domains do not bind calcium due to substitutions that disrupt their respective Ca(2+) binding loops. The cooperative binding of calcium to the EF-hand 2 domain following EF-hand 3 domain calcium binding requires myristoylation. Calcium binding to the 2 EF-hand domains induces exposure of the myristoyl group through a protein conformation change, this process known as the calcium-myristoyl switch facilitates binding to photoreceptor cell membranes.

Similarity. Belongs to the recoverin family.

RefSeq proteins (1): NP_002894* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF13499, PF13833

UniProt features (37 total): helix 11, binding site 10, domain 4, strand 4, initiator methionine 1, chain 1, site 1, modified residue 1, lipid moiety-binding region 1, disulfide bond 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2D8N	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35243-F1	84.11	0.38

Functional residue map

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

Catalytic / active sites (1): 192 (interaction with grk1)

Ligand- & substrate-binding residues (10): 80; 85; 110; 112; 114; 116; 121; 74; 76; 78

Post-translational modifications (2): 39, 2

Disulfide bonds (1): 39

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade

MSigDB gene sets: 108 (showing top): GOBP_PHOTOTRANSDUCTION, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_RADIATION, GOBP_DETECTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, MODULE_88, GOBP_DETECTION_OF_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_STIMULUS, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, GOBP_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, AGCTCCT_MIR28

GO Biological Process (5): signal transduction (GO:0007165), visual perception (GO:0007601), phototransduction (GO:0007602), regulation of signal transduction (GO:0009966), regulation of calcium ion transport (GO:0051924)

GO Molecular Function (3): calcium ion binding (GO:0005509), calcium sensitive guanylate cyclase activator activity (GO:0008048), metal ion binding (GO:0046872)

GO Cellular Component (6): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), dendrite (GO:0030425), perikaryon (GO:0043204), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
The phototransduction cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
signal transduction	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
detection of light stimulus	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
calcium ion transport	1
regulation of metal ion transport	1
metal ion binding	1
guanylate cyclase activator activity	1
cation binding	1
photoreceptor cell cilium	1
neuron projection	1
dendritic tree	1
neuronal cell body	1

Protein interactions and networks

STRING

2320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RCVRN	GRK7	Q8WTQ7	955
RCVRN	RHO	P08100	941
RCVRN	GRK1	Q15835	938
RCVRN	CRX	O43186	907
RCVRN	GUCY2D	Q02846	850
RCVRN	SAG	P10523	832
RCVRN	AMPH	P49418	819
RCVRN	OTX2	P32243	805
RCVRN	BIN1	O00499	782
RCVRN	VSX2	P58304	782
RCVRN	ZIC4	Q8N9L1	763
RCVRN	GAD2	Q05329	758
RCVRN	KCNC1	P48547	756
RCVRN	ARR3	P36575	751
RCVRN	PNMA2	Q9UL42	735

IntAct

13 interactions, top by confidence:

A	B	Type	Score
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
RCVRN	RAB9A	psi-mi:“MI:0914”(association)	0.530
COMMD10	VPS26C	psi-mi:“MI:0914”(association)	0.530
ARL4D	IFI30	psi-mi:“MI:0914”(association)	0.530
CXXC4	RCVRN	psi-mi:“MI:0915”(physical association)	0.400
IL15RA	RCVRN	psi-mi:“MI:0915”(physical association)	0.370
RCVRN	SMAD3	psi-mi:“MI:0915”(physical association)	0.370
TGFBR2	RCVRN	psi-mi:“MI:0915”(physical association)	0.370
RCVRN	GIT2	psi-mi:“MI:0915”(physical association)	0.370
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.350
PQBP1	RCVRN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): SCRN3 (Affinity Capture-MS), RAB9A (Affinity Capture-MS), C11orf73 (Affinity Capture-MS), RCVRN (Affinity Capture-MS), RCVRN (Affinity Capture-MS), RCVRN (Reconstituted Complex), GRK5 (Affinity Capture-Western), GRK6 (Affinity Capture-Western), CAV1 (Affinity Capture-Western), SCRN3 (Affinity Capture-MS), RCVRN (Affinity Capture-MS), RCVRN (Affinity Capture-MS), RCVRN (Affinity Capture-MS), C11orf73 (Affinity Capture-MS), RAB9A (Affinity Capture-MS)

ESM2 similar proteins: G5EDN6, O73761, P0CM54, P0CM55, P21457, P22728, P25296, P28470, P29104, P34057, P35243, P35332, P42322, P43080, P43081, P46065, P48451, P61022, P61023, P62760, P62761, P62762, P62763, P62764, P63098, P63099, P63100, P79880, P87072, Q24214, Q2TBI5, Q4R5F7, Q54MF3, Q55G87, Q5R6S5, Q5R7F0, Q5RD22, Q63810, Q63811, Q6BWS8

Diamond homologs: A0JN54, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, D3YWQ0, D3ZEY4, F1MAB7, O08560, O75912, O88673, P0CM54, P0CM55, P20192, P23743, P25296, P34057, P34125, P35243, P49619, P49620, P49621, P51556, P52429, P52824, P87072, Q01583, Q03603, Q09103, Q10024, Q13574, Q39017, Q6BWS8, Q6CGE6, Q6DT37, Q6FLU4

SIGNOR signaling

0 interactions.

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	20
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

369 predictions. Top by Δscore:

Variant	Effect	Δscore
17:9901002:T:A	donor_gain	1.0000
17:9901013:T:TA	donor_gain	1.0000
17:9901014:C:A	donor_gain	1.0000
17:9901096:ATAGC:A	acceptor_gain	1.0000
17:9901097:TAGC:T	acceptor_gain	1.0000
17:9901098:AGC:A	acceptor_gain	1.0000
17:9901098:AGCC:A	acceptor_loss	1.0000
17:9901099:GC:G	acceptor_gain	1.0000
17:9901100:CC:C	acceptor_gain	1.0000
17:9901101:C:CC	acceptor_gain	1.0000
17:9901101:CT:C	acceptor_loss	1.0000
17:9901102:T:C	acceptor_loss	1.0000
17:9901103:G:C	acceptor_gain	1.0000
17:9901107:C:CT	acceptor_gain	1.0000
17:9904796:TGAC:T	donor_loss	1.0000
17:9904797:GAC:G	donor_loss	1.0000
17:9904798:A:AC	donor_gain	1.0000
17:9904798:ACC:A	donor_loss	1.0000
17:9904799:C:CC	donor_gain	1.0000
17:9904819:T:TA	donor_gain	1.0000
17:9900891:G:A	donor_gain	0.9900
17:9900984:TTCAC:T	donor_loss	0.9900
17:9900985:TCA:T	donor_loss	0.9900
17:9900986:CACC:C	donor_loss	0.9900
17:9900987:ACC:A	donor_loss	0.9900
17:9900988:C:CA	donor_loss	0.9900
17:9900988:CCAT:C	donor_gain	0.9900
17:9901010:A:AC	donor_gain	0.9900
17:9901011:C:CC	donor_gain	0.9900
17:9901103:G:GC	acceptor_gain	0.9900

AlphaMissense

1345 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:9898183:A:G	F172S	0.998
17:9901030:C:G	R151P	0.998
17:9904863:G:C	F106L	0.998
17:9904863:G:T	F106L	0.998
17:9904865:A:G	F106L	0.998
17:9904969:C:G	R71P	0.998
17:9904971:G:C	F70L	0.998
17:9904971:G:T	F70L	0.998
17:9904973:A:G	F70L	0.998
17:9904871:A:G	W104R	0.997
17:9904871:A:T	W104R	0.997
17:9904932:G:C	F83L	0.997
17:9904932:G:T	F83L	0.997
17:9904933:A:G	F83S	0.997
17:9904934:A:G	F83L	0.997
17:9905035:A:G	F49S	0.997
17:9905076:G:C	F35L	0.997
17:9905076:G:T	F35L	0.997
17:9905078:A:G	F35L	0.997
17:9898182:G:C	F172L	0.996
17:9898182:G:T	F172L	0.996
17:9898184:A:G	F172L	0.996
17:9901100:C:G	A128P	0.996
17:9904831:A:T	I117N	0.996
17:9904858:A:G	L108P	0.996
17:9904869:C:A	W104C	0.996
17:9904869:C:G	W104C	0.996
17:9904915:G:T	A89D	0.996
17:9904921:A:T	V87D	0.996
17:9904972:A:G	F70S	0.996

dbSNP variants (sampled 300 via entrez): RS1000581302 (17:9906782 G>A), RS1000697346 (17:9906988 C>T), RS1000783060 (17:9895837 A>T), RS1000838758 (17:9896368 T>A), RS1001053550 (17:9896032 G>A,C), RS1001353468 (17:9902147 C>G,T), RS1001546157 (17:9906235 A>C), RS1002200003 (17:9902600 G>T), RS1002258819 (17:9897230 T>C), RS1003045879 (17:9898281 A>G), RS1003183970 (17:9899799 T>A,C), RS1003210655 (17:9905528 T>C), RS1003382947 (17:9899361 A>G), RS1003505720 (17:9905377 G>A,C,T), RS1003854930 (17:9902506 C>A)

Disease associations

OMIM: gene MIM:179618 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	3
tetrabromobisphenol S	decreases expression	1
tetrabromobisphenol A	decreases expression	1
nickel sulfate	decreases expression	1
2-palmitoylglycerol	increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Aluminum	affects binding, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Formaldehyde	decreases expression	1
Potassium Chloride	decreases response to substance, increases expression	1
Dronabinol	decreases response to substance, increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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