RP2

Summary

RP2 (RP2 activator of ARL3 GTPase, HGNC:10274) is a protein-coding gene on chromosome Xp11.3, encoding Protein XRP2 (O75695). Acts as a GTPase-activating protein (GAP) involved in trafficking between the Golgi and the ciliary membrane. It is haploinsufficient (ClinGen: sufficient evidence).

The RP2 locus has been implicated as one cause of X-linked retinitis pigmentosa. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. Progressive retinal degeneration may therefore be due to the accumulation of incorrectly-folded photoreceptor or neuron-specific tubulin isoforms followed by progressive cell death

Source: NCBI Gene 6102 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RP2-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 475 total — 116 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 1
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006915

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10274
Approved symbol	RP2
Name	RP2 activator of ARL3 GTPase
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Aliases	TBCCD2, NME10, NM23-H10
Ensembl gene	ENSG00000102218
Ensembl biotype	protein_coding
OMIM	300757
Entrez	6102

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000218340, ENST00000891112, ENST00000949778

RefSeq mRNA: 1 — MANE Select: NM_006915 NM_006915

CCDS: CCDS14270

Canonical transcript exons

ENST00000218340 — 5 exons

Exon	Start	End
ENSE00000669241	46853476	46854141
ENSE00000870084	46837043	46837202
ENSE00000870085	46859988	46860102
ENSE00001093035	46877505	46877590
ENSE00001093037	46879686	46882358

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 94.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.3570 / max 558.3100, expressed in 1779 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196141	14.8049	1681
196139	5.8289	1646
196140	1.7232	947

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.46	gold quality
mononuclear cell	CL:0000842	93.86	gold quality
leukocyte	CL:0000738	93.36	gold quality
jejunal mucosa	UBERON:0000399	89.78	gold quality
bone marrow	UBERON:0002371	88.59	gold quality
blood	UBERON:0000178	86.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.84	gold quality
ventricular zone	UBERON:0003053	84.75	gold quality
bone marrow cell	CL:0002092	84.47	gold quality
adrenal tissue	UBERON:0018303	84.08	gold quality
lower lobe of lung	UBERON:0008949	84.07	gold quality
colonic mucosa	UBERON:0000317	83.80	gold quality
vermiform appendix	UBERON:0001154	83.76	gold quality
gall bladder	UBERON:0002110	83.58	gold quality
choroid plexus epithelium	UBERON:0003911	83.56	gold quality
rectum	UBERON:0001052	83.20	gold quality
islet of Langerhans	UBERON:0000006	82.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.50	gold quality
placenta	UBERON:0001987	82.37	gold quality
stromal cell of endometrium	CL:0002255	81.83	gold quality
ganglionic eminence	UBERON:0004023	81.45	gold quality
trabecular bone tissue	UBERON:0002483	81.35	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.05	gold quality
epithelium of nasopharynx	UBERON:0001951	81.00	gold quality
calcaneal tendon	UBERON:0003701	80.81	gold quality
oral cavity	UBERON:0000167	80.59	gold quality
esophagus mucosa	UBERON:0002469	79.90	gold quality
palpebral conjunctiva	UBERON:0001812	79.85	gold quality
germinal epithelium of ovary	UBERON:0001304	79.16	gold quality
right lung	UBERON:0002167	79.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.33

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

172 targeting RP2, 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-126-5P	100.00	72.71	3180
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The mutation 358C–>T is useful in analyzing the function of RP2 protein and gene diagnosis of X-linked retinitis pigmentosa (XLRP). (PMID:11798852)
• functional overlap with tubulin-specific chaperone cofactor C (PMID:11847227)
• A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. (PMID:11992260)
• Patients with RP2 mutations had, on average, lower visual acuity but similar visual field area, final dark-adapted threshold, and 30-Hz ERG amplitude compared with those with RPGR mutations (PMID:14564670)
• Mutations in the RP2 gene is associated with X-linked retinitis pigmentosa (PMID:14566651)
• The data suggest that RP2 may have previously unrecognized roles as a DNA damage response factor and 3’ to 5’ exonuclease. (PMID:16457815)
• The N-terminal 34 residues and beta helix domain of RP2 are required for interaction with Arl3. (PMID:16472755)
• In this cohort of XLRP families, as has happened in previous studies, RP3 also seems to be the most prevalent form of XLRP, and, based on the results, the authors propose a four-step protocol for molecular diagnosis of XLRP families. (PMID:16936086)
• Three ORF15 mutations and one RP2 mutation in five Japanese retinitis pigmentosa families. (PMID:17093403)
• The proportion of RP2-mediated XLRP in the Danish population is higher and the proportion of RPGR-ORF15 is lower than reported in other studies. (PMID:17724181)
• RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs (PMID:18376416)
• A transversion (T>A) at position -9 in intron 3 of RP2 causes X-linked retinitis pigmentosa (XLRP) by altering the splicing pattern and highlights the pathogenicity of intronic variants. (PMID:19516003)
• Our results expand the frequency and spectrum of mutations at RPGR and RP2 as well as their associated clinical phenotypes in Chinese patients. (PMID:20021257)
• We propose that RP2 regulation of Arl3 is important for maintaining Golgi cohesion, facilitating the transport and docking of vesicles and thereby carrying proteins to the base of the photoreceptor connecting cilium for transport to the outer segment. (PMID:20106869)
• An identifiable phenotype for RP2-X-linked retinitis pigmentosa aids in clinical diagnosis and targeted genetic screening. (PMID:20625056)
• Data demonstrate that Importin beta2 is necessary for localization of retinitis pigmentosa 2 (RP2) to the primary cilium, and identify two distinct binding sites of RP2, which interact independently with Importin beta2. (PMID:21285245)
• data support a role for RP2 in facilitating the membrane association and traffic of Gbeta1, potentially prior to the formation of the obligate Gbeta:Ggamma heterodimer; combined with other recent evidence, this suggests that RP2 may co-operate with Arl3 and its effectors in the cilia-associated traffic of G proteins (PMID:22072390)
• The localization of RP2 to basal bodies and cilia in photoreceptors and kidney cells has linked RP2 dysfunction with ciliopathies. (PMID:22183373)
• Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. (PMID:23150612)
• Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these “adRP” families 19 had RPGR mutations, and two had RP2 mutations. (PMID:23372056)
• A novel frameshift mutation in RP2 was detected. This mutation was located in exon 2 of the RP2 gene: a nucleotide C was inserted at 111 (c.111insC, Fig. 1A), which caused a protein translation frameshift (PMID:24479636)
• The methylation state of CpG sites close to the RP2 core promoter (GAAA)n repeat serves as a proxy measurement of X-chromosome inactivation in human and non-human primates. (PMID:25078280)
• The ability of the restored RP2 protein level to reverse the observed cellular phenotypes in cells lacking RP2 indicates that translational read-through could be clinically beneficial for patients. (PMID:25292197)
• ellipsometric measurements of naRP2 demonstrated that its particular affinity for saturated phospholipids can be explained by its larger extent of insertion in this phospholipid monolayer compared to that in polyunsaturated phospholipid monolayers. (PMID:25844643)
• seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis (PMID:26806561)
• RP2 mutation would have a moderate pathogenic effect in photoreceptors carrying the mutation, causing abnormal outer segments, with the accumulation of lipofuscin similar to RDS/PRPH2 pattern dystrophy. (PMID:26885761)
• this study identifies ARL3 as a key player in prenylated protein trafficking in rod photoreceptor cells and establishes the potential role for ARL3 dysregulation in the pathogenesis of RP2-related forms of XLRP (PMID:26936825)
• Three mutations were identified in the ORF15 exon of RPGR. No RP2 mutations were found among the examined families. Mutation screening of RP patients is essential to understand the mechanism behind this disease and develop treatments (PMID:27323122)
• Three XLRP families (RP-001, RP-002, and RP-003), composed of 13 individuals, were reported in this study, and 2 different mutations were detcted We found 3 genetic variants: a novel mutation c.1591G>T in exon 14 and a novel polymorphism c.1105C>T in exon 10, resulting in p.Glu531* and p.Arg369Cys of RPGR gene, respectively, and one already known mutation c.413A>G in exon 2, resulting in a p.Glu138Gly of RP2 gene (PMID:27768226)
• We identified a novel causative mutation in RP2 from a single proband’s exome sequence data analysis. This study highlights the effectiveness of the whole-exome sequencing in the genetic diagnosis of X-linked retinitis pigmentosa, over the conventional sequencing methods. (PMID:27769321)
• Studies indicate taht the majority of patients with X-linked RP have mutations in the retinitis pigmentosa GTPase regulator (RPGR) or retinitis pigmentosa 2 protein (RP2) genes. (PMID:27911705)
• study also reveals a role of the C-terminal domain of RP2 in maintaining the overall protein stability. (PMID:28209709)
• four frameshift mutations including three novel mutations of c.1059 + 1 G > T, c.2002dupC and c.2236_2237del CT, as well as a previously reported mutation of c.2899delG were detected in the RPGR gene in the other four families. Our study further expands the mutation spectrum of RP2 and RPGR, and will be helpful for further study molecular pathogenesis of X-linked retinitis pigmentosa. (PMID:28294154)
• We utilized a structure-based approach to pinpoint the binding interface to a strictly conserved cluster of residues on the surface of RP2 that spans both the C- and N-terminal domains of the protein, and which is structurally distinct from the ARL3-binding site.RP2 is a positive regulator of cell motility in vitro, recruiting OSTF1 to the cell membrane and preventing its interaction with the migration regulator Myo1E. (PMID:29361551)
• Data identified a novel RP2 missense mutation Q158P in a Chinese family with X-linked retinitis pigmentosa (XLRP). RP2 Q158P located in the TBCC domain and destabilized RP2 protein in ARPE-19 cells. (PMID:31071385)
• Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants. (PMID:32244552)
• RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype-phenotype association. (PMID:32875684)
• Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials. (PMID:34208932)
• Genotypic and phenotypic characterisation of RP2- and RPGR-associated X-linked inherited retinal dystrophy, including female manifestations. (PMID:36882936)
• RP2-Associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History in a Large Cohort of Female Carriers. (PMID:37977507)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rp2	ENSDARG00000044339
mus_musculus	Rp2	ENSMUSG00000060090
rattus_norvegicus	Rp2	ENSRNOG00000025428
caenorhabditis_elegans		WBGENE00019536

Protein

Protein identifiers

Protein XRP2 — O75695 (reviewed: O75695)

All UniProt accessions (2): O75695, A0A1B2JLU2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a GTPase-activating protein (GAP) involved in trafficking between the Golgi and the ciliary membrane. Involved in localization of proteins, such as NPHP3, to the cilium membrane by inducing hydrolysis of GTP ARL3, leading to the release of UNC119 (or UNC119B). Acts as a GTPase-activating protein (GAP) for tubulin in concert with tubulin-specific chaperone C, but does not enhance tubulin heterodimerization. Acts as a guanine nucleotide dissociation inhibitor towards ADP-ribosylation factor-like proteins.

Subunit / interactions. Found in a complex with ARL3, RP2 and UNC119 (or UNC119B); RP2 induces hydrolysis of GTP ARL3 in the complex, leading to the release of UNC119 (or UNC119B). Interacts with ARL3; interaction is direct and stimulated with the activated GTP-bound form of ARL3.

Subcellular location. Cell membrane. Cell projection. Cilium.

Tissue specificity. Ubiquitous. Expressed in the rod and cone photoreceptors, extending from the tips of the outer segment (OS) through the inner segment (IS) and outer nuclear layer (ONL) and into the synaptic terminals of the outer plexiform layer (ONL). Also detected in the bipolar, horizontal and amacrine cells in the inner nuclear layer (INL), extending to the inner plexiform layer (IPL) and though the ganglion cell layer (GCL) and into the nerve fiber layer (NFL) (at protein level).

Post-translational modifications. Myristoylated on Gly-2; which may be required for membrane targeting. Palmitoylated on Cys-3; which may be required for plasma membrane targeting. Mutation of Cys-3 targets the protein to internal membranes.

Disease relevance. Retinitis pigmentosa 2 (RP2) [MIM:312600] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TBCC family.

RefSeq proteins (1): NP_008846* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006599	CARP_motif	Domain
IPR012945	Tubulin-bd_cofactor_C_dom	Domain
IPR016098	CAP/MinC_C	Homologous_superfamily
IPR017901	C-CAP_CF_C-like	Domain
IPR036223	CAP_C_sf	Homologous_superfamily
IPR036850	NDK-like_dom_sf	Homologous_superfamily
IPR039093	XRP2	Family

Pfam: PF07986

UniProt features (66 total): sequence variant 16, strand 16, mutagenesis site 13, helix 9, compositionally biased region 2, binding site 2, lipid moiety-binding region 2, initiator methionine 1, chain 1, domain 1, region of interest 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3BH7	X-RAY DIFFRACTION	1.9
2BX6	X-RAY DIFFRACTION	2.1
3BH6	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75695-F1	91.64	0.86

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 (2): 98–99; 115–118

Post-translational modifications (2): 2, 3

Mutagenesis-validated functional residues (13):

Position	Phenotype
2	loss of membrane association.
3	targeting to internal membranes. loss of targeting to the plasma membrane.
28	reduces affinity for mouse arl3; when associated with a-29.
29	reduces affinity for mouse arl3; when associated with a-28.
31	does not reduce affinity for mouse arl3; when associated with a-32.
32	does not reduce affinity for mouse arl3; when associated with a-31.
101	reduces affinity for mouse arl3.
115	reduces affinity for mouse arl3.
116	reduces affinity and gtp-hydrolysis rate for mouse arl3.
118	reduces affinity and gtp-hydrolysis rate for mouse arl3.
120	reduces affinity for mouse arl3; when associated with s-121.
121	reduces affinity for mouse arl3; when associated with h-120.
177	reduces affinity and gtp-hydrolysis rate for mouse arl3.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5624138	Trafficking of myristoylated proteins to the cilium

MSigDB gene sets: 274 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, CROONQUIST_NRAS_SIGNALING_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_PROTEIN_MATURATION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_CILIUM_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, GOBP_PROTEIN_FOLDING

GO Biological Process (5): protein folding (GO:0006457), post-Golgi vesicle-mediated transport (GO:0006892), visual perception (GO:0007601), protein transport (GO:0015031), cilium assembly (GO:0060271)

GO Molecular Function (6): magnesium ion binding (GO:0000287), GTPase activator activity (GO:0005096), GTP binding (GO:0005525), obsolete unfolded protein binding (GO:0051082), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (18): acrosomal vesicle (GO:0001669), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centriole (GO:0005814), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), nuclear body (GO:0016604), cytoplasmic vesicle (GO:0031410), ciliary basal body (GO:0036064), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), periciliary membrane compartment (GO:1990075), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cargo trafficking to the periciliary membrane	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
cytoplasm	3
sperm flagellum	3
microtubule organizing center	2
intracellular membraneless organelle	2
cellular process	1
protein maturation	1
Golgi vesicle transport	1
sensory perception of light stimulus	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
metal ion binding	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
secretory granule	1
nuclear lumen	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
nucleoplasm	1

Protein interactions and networks

STRING

644 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RP2	NME9	Q86XW9	645
RP2	NME3	Q13232	626
RP2	NME5	P56597	621
RP2	NME6	O75414	620
RP2	ARL3	P36405	604
RP2	NME7	Q9Y5B8	592
RP2	NME1	P15531	583
RP2	NME4	O00746	582
RP2	NME2	P22392	571
RP2	ARL2	P36404	465
RP2	MKS1	Q9NXB0	446
RP2	NPHP1	O15259	423
RP2	NME8	Q8N427	410
RP2	ARL13A	Q5H913	399
RP2	B9D2	Q9BPU9	395

IntAct

94 interactions, top by confidence:

A	B	Type	Score
RAMAC	RNMT	psi-mi:“MI:0914”(association)	0.810
RP2	Arl3	psi-mi:“MI:0407”(direct interaction)	0.740
Arl3	RP2	psi-mi:“MI:0407”(direct interaction)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
OSTF1	RP2	psi-mi:“MI:0914”(association)	0.640
ARL3	RP2	psi-mi:“MI:0915”(physical association)	0.620
ARL3	RP2	psi-mi:“MI:0914”(association)	0.620
	RP2	psi-mi:“MI:0915”(physical association)	0.560
RP2	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
RP2	WDR83	psi-mi:“MI:0915”(physical association)	0.530
OSTF1	CHMP2A	psi-mi:“MI:0914”(association)	0.530
POMK	CLGN	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
RP2	Arl2	psi-mi:“MI:0407”(direct interaction)	0.440
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
		psi-mi:“MI:0914”(association)	0.350

BioGRID (173): RP2 (Affinity Capture-MS), RP2 (Affinity Capture-MS), RP2 (Affinity Capture-MS), XPO7 (Affinity Capture-MS), IPO7 (Affinity Capture-MS), TNPO2 (Affinity Capture-MS), NMT1 (Affinity Capture-MS), GLMN (Affinity Capture-MS), CSE1L (Affinity Capture-MS), TSC2 (Affinity Capture-MS), XPO4 (Affinity Capture-MS), KIAA0368 (Affinity Capture-MS), CSTF2 (Affinity Capture-MS), DMXL2 (Affinity Capture-MS), PDS5A (Affinity Capture-MS)

ESM2 similar proteins: A0KHG0, A1S4N7, A1TQ21, A3QGA6, A4SQI5, A4SYV8, A5PJI7, A7SGU3, A8FY45, A8H6L9, A8WWC0, A9IR78, B1Y6E5, B4F2D6, C4L868, F4JIP6, O60064, O75695, P0A4U8, P0A4U9, P47823, P52416, P70541, Q085E5, Q0VFM6, Q12NZ0, Q13144, Q21WT2, Q28DR7, Q4R6T3, Q502J7, Q54XU5, Q5QXS9, Q64350, Q66KG5, Q6DKE9, Q6GM65, Q6GMK8, Q7SXP8, Q7W8Y2

Diamond homologs: F1QC45, O75695, Q5ZHN4, Q8AVX5, Q9EPK2, Q9SMR2, Q15814, Q3SZE9, Q54PY1, Q5R5J7, Q8VCN9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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
Neutrophil degranulation	11	4.2×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
transmembrane transport	6	12.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	116
Likely pathogenic	46
Uncertain significance	134
Likely benign	67
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10545	NM_006915.3(RP2):c.76C>T (p.Gln26Ter)	Pathogenic
10547	NM_006915.3(RP2):c.453C>G (p.Tyr151Ter)	Pathogenic
10548	NM_006915.3(RP2):c.453del (p.Tyr152Ilefs*4)	Pathogenic
10549	NM_006915.3(RP2):c.353G>T (p.Arg118Leu)	Pathogenic
10551	NM_006915.3(RP2):c.358C>T (p.Arg120Ter)	Pathogenic
1067693	NM_006915.3(RP2):c.284C>T (p.Pro95Leu)	Pathogenic
1068681	NM_006915.3(RP2):c.450G>A (p.Trp150Ter)	Pathogenic
1068927	NM_006915.3(RP2):c.255del (p.Cys86fs)	Pathogenic
1072062	NM_006915.3(RP2):c.736del (p.Thr246fs)	Pathogenic
1072830	NC_000023.10:g.(?46508101)(46739204_?)del	Pathogenic
1073571	NM_006915.3(RP2):c.700G>T (p.Glu234Ter)	Pathogenic
1074380	NM_006915.3(RP2):c.243_258dup (p.Thr87delinsTyrHisTer)	Pathogenic
1075432	NM_006915.3(RP2):c.867_870del (p.Pro290fs)	Pathogenic
1075685	NM_006915.3(RP2):c.91C>T (p.Gln31Ter)	Pathogenic
1076306	NM_006915.3(RP2):c.519_520insGTTA (p.Ile174fs)	Pathogenic
1184894	NM_006915.3(RP2):c.838del (p.Val280fs)	Pathogenic
1213906	NM_006915.3(RP2):c.333_334del (p.Leu112fs)	Pathogenic
1213909	NM_006915.3(RP2):c.465_468dup (p.Phe157fs)	Pathogenic
1352266	NM_006915.3(RP2):c.557G>A (p.Trp186Ter)	Pathogenic
1353451	NM_006915.3(RP2):c.249del (p.Ile83fs)	Pathogenic
1353603	NM_006915.3(RP2):c.175G>T (p.Gly59Ter)	Pathogenic
1354932	NM_006915.3(RP2):c.832C>T (p.Gln278Ter)	Pathogenic
1368127	NM_006915.3(RP2):c.385_386del (p.Leu129fs)	Pathogenic
1368936	NM_006915.3(RP2):c.513del (p.Thr170_Trp171insTer)	Pathogenic
1378935	NM_006915.3(RP2):c.719del (p.Leu240fs)	Pathogenic
1389912	NM_006915.3(RP2):c.542_543del (p.Ser181fs)	Pathogenic
1404865	NM_006915.3(RP2):c.843del (p.Arg282fs)	Pathogenic
1405673	NM_006915.3(RP2):c.852dup (p.Ala285fs)	Pathogenic
1417282	NM_006915.3(RP2):c.800del (p.Thr267fs)	Pathogenic
1426488	NM_006915.3(RP2):c.239_240del (p.Thr80fs)	Pathogenic

SpliceAI

716 predictions. Top by Δscore:

Variant	Effect	Δscore
X:46853471:T:A	acceptor_gain	1.0000
X:46853471:TGCA:T	acceptor_loss	1.0000
X:46853472:GCAG:G	acceptor_loss	1.0000
X:46853473:CA:C	acceptor_loss	1.0000
X:46853474:A:AG	acceptor_gain	1.0000
X:46853474:AG:A	acceptor_gain	1.0000
X:46853474:AGGT:A	acceptor_loss	1.0000
X:46853474:AGGTT:A	acceptor_gain	1.0000
X:46853475:G:GG	acceptor_gain	1.0000
X:46853475:GG:G	acceptor_gain	1.0000
X:46853475:GGT:G	acceptor_gain	1.0000
X:46853475:GGTT:G	acceptor_gain	1.0000
X:46853475:GGTTG:G	acceptor_gain	1.0000
X:46877586:CCAAG:C	donor_loss	1.0000
X:46877587:CAAG:C	donor_loss	1.0000
X:46877588:AAG:A	donor_loss	1.0000
X:46877589:AGG:A	donor_loss	1.0000
X:46877590:GGTAC:G	donor_loss	1.0000
X:46879675:A:AG	acceptor_gain	1.0000
X:46879679:A:AG	acceptor_gain	1.0000
X:46879680:A:G	acceptor_gain	1.0000
X:46879681:A:AG	acceptor_gain	1.0000
X:46879683:TA:T	acceptor_loss	1.0000
X:46879684:A:AG	acceptor_gain	1.0000
X:46879684:A:AT	acceptor_loss	1.0000
X:46879684:AGAT:A	acceptor_gain	1.0000
X:46879685:G:GG	acceptor_gain	1.0000
X:46879685:GAT:G	acceptor_gain	1.0000
X:46879685:GATG:G	acceptor_gain	1.0000
X:46879685:GATGT:G	acceptor_gain	1.0000

AlphaMissense

2341 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:46853668:A:C	S99R	0.998
X:46853670:C:A	S99R	0.998
X:46853670:C:G	S99R	0.998
X:46853681:G:C	R103P	0.998
X:46853726:G:C	R118P	0.998
X:46853884:T:A	W171R	0.998
X:46853884:T:C	W171R	0.998
X:46853902:T:C	F177L	0.998
X:46853904:T:A	F177L	0.998
X:46853904:T:G	F177L	0.998
X:46853725:C:A	R118S	0.997
X:46853725:C:G	R118G	0.997
X:46853732:G:C	R120P	0.997
X:46837187:G:C	W29C	0.996
X:46837187:G:T	W29C	0.996
X:46853777:C:A	P135H	0.995
X:46853787:G:C	E138D	0.995
X:46853787:G:T	E138D	0.995
X:46837185:T:A	W29R	0.994
X:46837185:T:C	W29R	0.994
X:46853631:T:G	C86W	0.994
X:46853715:C:G	C114W	0.994
X:46853721:A:C	Q116H	0.994
X:46853721:A:T	Q116H	0.994
X:46853737:T:C	C122R	0.994
X:46853739:T:G	C122W	0.994
X:46853766:T:G	C131W	0.994
X:46853777:C:G	P135R	0.994
X:46853713:T:C	C114R	0.993
X:46854035:T:A	V221D	0.993

dbSNP variants (sampled 300 via entrez): RS1000131207 (X:46845025 G>T), RS1000264173 (X:46854908 G>A,T), RS1000318139 (X:46844391 A>G), RS1000426939 (X:46853807 T>C), RS1000713592 (X:46875167 C>T), RS1001005360 (X:46875882 T>C), RS1001118750 (X:46836882 A>G), RS1001190229 (X:46847620 A>G), RS1001332194 (X:46857058 T>C), RS1001446386 (X:46856465 G>T), RS1001447344 (X:46867225 C>G,T), RS1001617316 (X:46878249 C>T), RS1001724882 (X:46847031 G>T), RS1001960502 (X:46866753 C>T), RS1002031309 (X:46839566 A>T)

Disease associations

OMIM: gene MIM:300757 | disease phenotypes: MIM:312600, MIM:268000, MIM:300029, MIM:248200, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
RP2-related retinopathy	Definitive	X-linked
retinitis pigmentosa 2	Definitive	X-linked
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
RP2-related retinopathy	Definitive	XL

Mondo (8): retinitis pigmentosa 2 (MONDO:0010723), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), retinitis pigmentosa 3 (MONDO:0010227), retinal disorder (MONDO:0005283), Stargardt disease (MONDO:0019353), Leber congenital amaurosis (MONDO:0018998), RP2-related retinopathy (MONDO:0100442)

Orphanet (4): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Stargardt disease (Orphanet:827), Leber congenital amaurosis (Orphanet:65)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
C567523	Retinitis Pigmentosa 2 (supp.)
C564520	Retinitis Pigmentosa 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, decreases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases expression	2
dicrotophos	decreases expression	1
beauvericin	increases expression, affects cotreatment	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	decreases expression	1
cupric oxide	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
enniatins	increases expression, affects cotreatment	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Calcitriol	increases expression	1
Cisplatin	increases expression	1
Diethylhexyl Phthalate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa