RHO

Summary

RHO (rhodopsin, HGNC:10012) is a protein-coding gene on chromosome 3q22.1, encoding Rhodopsin (P08100). Photoreceptor required for image-forming vision at low light intensity.

The protein encoded by this gene is found in rod cells in the back of the eye and is essential for vision in low-light conditions. The encoded protein binds to 11-cis retinal and is activated when light hits the retinal molecule. Defects in this gene are a cause of congenital stationary night blindness.

Source: NCBI Gene 6010 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RHO-related retinopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 660 total — 86 pathogenic, 63 likely-pathogenic
• Phenotypes (HPO): 61
• Druggable target: yes
• MANE Select transcript: NM_000539

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10012
Approved symbol	RHO
Name	rhodopsin
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	OPN2, CSNBAD1
Ensembl gene	ENSG00000163914
Ensembl biotype	protein_coding
OMIM	180380
Entrez	6010

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000296271

RefSeq mRNA: 1 — MANE Select: NM_000539 NM_000539

CCDS: CCDS3063

Canonical transcript exons

ENST00000296271 — 5 exons

Exon	Start	End
ENSE00001079597	129528639	129529094
ENSE00001079599	129533608	129535344
ENSE00001152199	129532533	129532772
ENSE00001152205	129532251	129532416
ENSE00001152211	129530876	129531044

Expression profiles

Bgee: expression breadth broad, 38 present calls, max score 92.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.0054 / max 6917.4600, expressed in 6 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38537	7.0027	6
38536	0.0027	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
optic choroid	UBERON:0001776	92.00	gold quality
neuron projection bundle connecting eye with brain	UBERON:0004904	87.50	gold quality
diaphragm	UBERON:0001103	86.78	gold quality
olfactory bulb	UBERON:0002264	83.40	gold quality
type B pancreatic cell	CL:0000169	83.09	gold quality
triceps brachii	UBERON:0001509	81.21	gold quality
buccal mucosa cell	CL:0002336	81.18	silver quality
gluteal muscle	UBERON:0002000	80.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.57	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.76	gold quality
biceps brachii	UBERON:0001507	77.33	gold quality
mucosa of urinary bladder	UBERON:0001259	75.80	gold quality
left ventricle myocardium	UBERON:0006566	75.77	gold quality
cardiac muscle of right atrium	UBERON:0003379	75.21	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.53	gold quality
superficial temporal artery	UBERON:0001614	74.32	gold quality
retina	UBERON:0000966	73.61	gold quality
pigmented layer of retina	UBERON:0001782	73.60	gold quality
tongue squamous epithelium	UBERON:0006919	73.46	gold quality
secondary oocyte	CL:0000655	72.46	silver quality
myocardium	UBERON:0002349	72.26	gold quality
nasal cavity epithelium	UBERON:0005384	71.76	gold quality
heart right ventricle	UBERON:0002080	70.94	gold quality
orbitofrontal cortex	UBERON:0004167	70.94	gold quality
inferior olivary complex	UBERON:0002127	70.82	gold quality
lower lobe of lung	UBERON:0008949	70.62	silver quality
gingiva	UBERON:0001828	70.24	gold quality
gingival epithelium	UBERON:0001949	69.93	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	69.87	gold quality
thymus	UBERON:0002370	69.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	24018.76
E-GEOD-98556	yes	18703.65
E-GEOD-137537	yes	9864.21
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting RHO, 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-8485	100.00	77.57	4731
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-208A-5P	99.42	70.83	1913

Literature-anchored findings (GeneRIF, showing 40)

• Mutations of codons 345 and 347 have been found which are associated with retinitis pigmentosa. (PMID:11910130)
• Comparison of rhodopsin mutation in dog and human for retinitis pigmentosa. (PMID:11972042)
• A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. (PMID:12091393)
• The eye photoreceptor protein rhodopsin. Structural implications for retinal disease. Review. (PMID:12297272)
• Retinitis pigmentosa-associated mutations associated with three membrane-located cysteine residues present three different biochemical phenotypes (PMID:12359230)
• The rhodopsin night blindness mutant G90D has a previously unreported phenotype of slow binding of the 11-cis-retinal chromophore. (PMID:12590587)
• the transformation of rhodopsin to signaling metarhodopsin (Meta) II after retinal photoisomerization is due to a conserved motif (PMID:12601165)
• mutations in rhodopsin could result in faster activation kinetics and play a role in retinitis pigmentosa (PMID:12646201)
• data provide evidence that cytoplasmic chaperones HSJ1a and HSJ1b when targeted to the endoplasmic reticulum can influence the folding and processing of rhodopsin (PMID:12754272)
• identification of rhodopsin mutations L125R and A164V which perturb critical interhelical interactions (PMID:12871954)
• A homozygous rhodopsin splice-site mutation is associated with retinitis pigmentosa (PMID:14566652)
• Impaired endocytic activity may underlie the pathogenesis of retinitis pigmentosa caused by class III rhodopsin mutations. (PMID:15232620)
• dominant negative effect on conformational maturation that may underlie the dominant inheritance of autosomal dominant retinitis pigmentosa (PMID:15509574)
• Our results demonstrate that mutations in PRPF31 gene affect rhodopsin (RHO) pre-mRNA splicing and reveal a link between PRPF31 and RHO, two major genes in autosomal dominant retinitis pigmentosa. (PMID:15659613)
• the autosomal dominant RP family showed the rhodopsin locus segregating concordantly with the disease. (PMID:15726226)
• A recurrent missense mutation, 512C>T (P171L), was detected in a Chinese family with autosomal dominant retinitis pigmentosa. (PMID:15793783)
• Several different potential gain-of-function mechanisms for rhodopsin in autosomal dominant retinis pigmentosa.are described and discussed (PMID:15823756)
• Rhodopsin mutations result in autosomal dominant retinitis pigmentosa (ADRP), the most frequent being Proline-23 substitution by histidine (RhoP23H). (PMID:16049034)
• Frequency and pattern of rhodopsin point mutations in Chinese patients with autosomal dominant retinitis pigmentosa. (PMID:16229860)
• Different amino acid substitutions at position 90 of rhodopsin can lead to night blindness or retinitis pigmentosa. The data suggest that the property of the substituted amino acid distinguishes between the phenotypes. (PMID:16565402)
• Transgenic rats were trained to find a one-way exit door leading into their home cage, based on distinguishing between two different visual alternatives. (PMID:17289151)
• Six of 12 families had an RHO mutation. The mutation V345M and the novel mutation 1003delG both caused classical Retinitis Pigmentosa. (PMID:17488458)
• Japanese RHO locus is comprised of eight major haplotypes. Retinitis pigmentosa-associated haplotype was not identified. (PMID:17653048)
• The novel R252P mutation in the RHO gene was found in the patients with retinitis pigmentosa from Bashkortostan. (PMID:17936999)
• two models of interaction for the human S-arrestin/rhodopsin complex (PMID:18175313)
• L:M cone ratio will be similar among populations that share the same X-chromosome opsin gene array organization. (PMID:18318631)
• Retinal laminar abnormalities were present in both classes of RHO-ADRP and were related to the severity of colocalized vision loss. (PMID:18385078)
• Mutant opsin activates transducin constitutively, which is a consistent and common feature of all congenital stationary night blindness-associated rhodopsin mutation. (PMID:18487375)
• RHO, PRPF31, RP1, and IMPDH1 were screened and causative mutations were identifiedin 4% of isolated and 2% of autosomal dominant forms of retinitis pigmentosa patients from India. (PMID:18552984)
• a probable high-penetrance disease-causing sequence variation in the rhodopsin gene, a heterozygous ACG>ATG nucleotide substitution resulting in a Thr17Met amino acid change, was detected in a proband with unusual regionalized retinochoroidopathy (PMID:18698306)
• IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA (PMID:18974094)
• Patients with RHO (D190N) autosomal dominant retinitis pigmentosa (adRP) can show classic signs of retinitis pigmentosa on fundus examination and may be able to maintain good central visual acuity into adulthood. (PMID:19085385)
• Two structurally conserved low-affinity zinc coordination motifs, located among a cluster of retinitis pigmentosa mutations in the intradiscal loop region, mediate dose-dependent rhodopsin destabilization. (PMID:19206210)
• no evidence for an association between telomere length and the severity of retinitis pigmentosa in patients with the Pro23His rhodopsin mutation (PMID:19325938)
• Thrombin promotes ATP release from A549 cells via Rho- and Ca(2+)-dependent activation of connexin/pannexin hemichannels. (PMID:19439413)
• Immunoreactivity to anti-rhodopsin antibodies was seen in human epidermis (except the basal layer) & reconstructed skin. The mRNA was seen in total RNA from skin. Neither immunoreactivity nor mRNA expression was seen in cultured human keratinocytes. (PMID:19493002)
• Mutations in PRPF31, RHO, and PRPH2 were found in low frequencies (1 of 9 autosomal dominant RP families) in Chinese patients, and the PRPF31 and PRPH2 truncating mutations were novel. (PMID:19506198)
• Study shows that a strong perturbation of the retinal (13)C12 chemical shift observed in rhodopsin is reduced in wild-type metarhodopsin II and in the E181Q mutant of rhodopsin. (PMID:19795853)
• Data show that demonstrate that Cnx preferentially associates with misfolded mutant opsins associated with retinitis pigmentosa. (PMID:19801547)
• Studies indicate that activation of the model GPCR, rhodopsin, is triggered by photoisomerization of its retinal ligand. (PMID:19836958)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rho	ENSDARG00000002193
danio_rerio	rhol	ENSDARG00000070666
		ENSDARG00000103574
danio_rerio	exorh	ENSDARG00000111860
mus_musculus	Rho	ENSMUSG00000030324
rattus_norvegicus	Rho	ENSRNOG00000011144

Paralogs (9): OPN3 (ENSG00000054277), OPN1LW (ENSG00000102076), OPN4 (ENSG00000122375), OPN5 (ENSG00000124818), OPN1SW (ENSG00000128617), OPN1MW2 (ENSG00000166160), RRH (ENSG00000180245), OPN1MW (ENSG00000268221), OPN1MW3 (ENSG00000269433)

Protein

Protein identifiers

Rhodopsin — P08100 (reviewed: P08100)

Alternative names: Opsin-2

All UniProt accessions (1): P08100

UniProt curated annotations — full annotation on UniProt →

Function. Photoreceptor required for image-forming vision at low light intensity. Required for photoreceptor cell viability after birth. Light-induced isomerization of the chromophore 11-cis-retinal to all-trans-retinal triggers a conformational change that activates signaling via G-proteins. Subsequent receptor phosphorylation mediates displacement of the bound G-protein alpha subunit by the arrestin SAG and terminates signaling.

Subunit / interactions. Homodimer. 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 with GRK1. Interacts (phosphorylated form) with SAG. Interacts with GNAT1. Interacts with GNAT3. SAG and G-proteins compete for a common binding site. Interacts with PRCD; the interaction promotes PRCD stability. Forms a complex with ASAP1 and ARF4. Forms a complex with ASAP1, RAB11A, Rabin8/RAB3IP, ARF4 and RAB11FIP3; the complex regulates Golgi-to-cilia rhodopsin/RHO transport in photoreceptors.

Subcellular location. Membrane. Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. Rod shaped photoreceptor cells which mediate vision in dim light.

Post-translational modifications. Phosphorylated on some or all of the serine and threonine residues present in the C-terminal region. After activation by light, phosphorylated by GRK1 (in vitro). Contains one covalently linked retinal chromophore. Upon light absorption, the covalently bound 11-cis-retinal is converted to all-trans-retinal. After hydrolysis of the Schiff base and release of the covalently bound all-trans-retinal, active rhodopsin is regenerated by binding of a fresh molecule of 11-cis-retinal.

Disease relevance. Retinitis pigmentosa 4 (RP4) [MIM:613731] 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. Night blindness, congenital stationary, autosomal dominant 1 (CSNBAD1) [MIM:610445] A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 1 family. Opsin subfamily.

RefSeq proteins (1): NP_000530* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000732	Rhodopsin	Family
IPR001760	Opsin	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR019477	Rhodopsin_N	Domain
IPR027430	Retinal_BS	Binding_site
IPR050125	GPCR_opsins	Family

Pfam: PF00001, PF10413

UniProt features (144 total): sequence variant 75, helix 13, turn 9, topological domain 8, strand 8, modified residue 8, transmembrane region 7, mutagenesis site 5, binding site 2, lipid moiety-binding region 2, glycosylation site 2, chain 1, region of interest 1, short sequence motif 1, site 1, disulfide bond 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5W0P	X-RAY DIFFRACTION	3.01
4ZWJ	X-RAY DIFFRACTION	3.3
6CMO	ELECTRON MICROSCOPY	4.5
5DGY	X-RAY DIFFRACTION	7.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08100-F1	89.18	0.68

Antibody-complex structures (SAbDab): 1 — 6CMO

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): 113 (plays an important role in the conformation switch to the active conformation)

Ligand- & substrate-binding residues (2): 201; 279

Post-translational modifications (10): 1, 296, 334, 336, 338, 340, 342, 343, 322, 323

Disulfide bonds (1): 110–187

Glycosylation sites (2): 2, 15

Mutagenesis-validated functional residues (5):

Position	Phenotype
113	induces a conformation change that promotes interaction with grk1 and sag; when associated with y-257.
257	induces a conformation change that promotes interaction with grk1 and sag; when associated with q-113.
336–340	loss of phosphorylation sites and decreased interaction with sag.
336–338	loss of phosphorylation sites and decreased interaction with sag; when associated with a-343.
343	loss of phosphorylation sites and decreased interaction with sag; when associated with 336-a–a-338.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2453902	The canonical retinoid cycle in rods (twilight vision)
R-HSA-2485179	Activation of the phototransduction cascade
R-HSA-2514859	Inactivation, recovery and regulation of the phototransduction cascade
R-HSA-418594	G alpha (i) signalling events
R-HSA-419771	Opsins
R-HSA-5620916	VxPx cargo-targeting to cilium

MSigDB gene sets: 268 (showing top): GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, BROWNE_HCMV_INFECTION_8HR_UP, LFA1_Q6, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AAGCCAT_MIR135A_MIR135B, GOBP_PHOTOTRANSDUCTION, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_NEURAL_RETINA_DEVELOPMENT, CHESLER_BRAIN_D6MIT150_QTL_CIS, GOBP_TAXIS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_DETECTION_OF_TEMPERATURE_STIMULUS, FOSTER_TOLERANT_MACROPHAGE_DN

GO Biological Process (20): microtubule cytoskeleton organization (GO:0000226), G protein-coupled receptor signaling pathway (GO:0007186), visual perception (GO:0007601), phototransduction (GO:0007602), phototransduction, visible light (GO:0007603), response to light intensity (GO:0009642), gene expression (GO:0010467), absorption of visible light (GO:0016038), G protein-coupled opsin signaling pathway (GO:0016056), thermotaxis (GO:0043052), photoreceptor cell maintenance (GO:0045494), detection of temperature stimulus involved in thermoception (GO:0050960), cellular response to light stimulus (GO:0071482), podosome assembly (GO:0071800), rod bipolar cell differentiation (GO:1904389), signal transduction (GO:0007165), response to light stimulus (GO:0009416), detection of light stimulus (GO:0009583), sensory perception of light stimulus (GO:0050953), retina development in camera-type eye (GO:0060041)

GO Molecular Function (6): G protein-coupled receptor activity (GO:0004930), 11-cis retinal binding (GO:0005502), G protein-coupled photoreceptor activity (GO:0008020), metal ion binding (GO:0046872), protein binding (GO:0005515), photoreceptor activity (GO:0009881)

GO Cellular Component (16): Golgi membrane (GO:0000139), photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane (GO:0016020), Golgi-associated vesicle membrane (GO:0030660), photoreceptor outer segment membrane (GO:0042622), ciliary membrane (GO:0060170), photoreceptor inner segment membrane (GO:0060342), sperm midpiece (GO:0097225), photoreceptor disc membrane (GO:0097381), rod photoreceptor outer segment (GO:0120200), sperm head plasma membrane (GO:1990913), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
The phototransduction cascade	2
Visual phototransduction	1
GPCR downstream signalling	1
Class A/1 (Rhodopsin-like receptors)	1
Cargo trafficking to the periciliary membrane	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
response to light stimulus	3
bounding membrane of organelle	3
photoreceptor outer segment	3
G protein-coupled receptor activity	2
signal transduction	2
phototransduction	2
detection of visible light	2
G protein-coupled receptor signaling pathway	2
plasma membrane region	2
cytoskeleton organization	1
microtubule-based process	1
sensory perception of light stimulus	1
detection of light stimulus	1
macromolecule biosynthetic process	1
light absorption	1
phototransduction, visible light	1
cellular response to light stimulus	1
response to temperature stimulus	1
taxis	1
retina homeostasis	1
multicellular organismal process	1
thermoception	1
detection of temperature stimulus involved in sensory perception	1
cellular response to radiation	1
protein-containing complex assembly	1
plasma membrane bounded cell projection assembly	1
retinal bipolar neuron differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to radiation	1
detection of external stimulus	1
detection of abiotic stimulus	1
sensory perception	1
camera-type eye development	1
anatomical structure development	1
transmembrane signaling receptor activity	1

Protein interactions and networks

STRING

3556 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHO	SAG	P10523	999
RHO	GRK7	Q8WTQ7	994
RHO	GRK1	Q15835	993
RHO	ARR3	P36575	987
RHO	GNAT1	P11488	951
RHO	ARRB1	P49407	944
RHO	RCVRN	P35243	941
RHO	CRX	O43186	927
RHO	PRPH2	P23942	927
RHO	RPE65	Q16518	912
RHO	CALM1	P02593	902
RHO	CALML3	P27482	902
RHO	CALML6	Q8TD86	902
RHO	CALML4	Q96GE6	902
RHO	CALML5	Q9NZT1	901

IntAct

8 interactions, top by confidence:

A	B	Type	Score
RHO	CD79A	psi-mi:“MI:0915”(physical association)	0.560
RHO	ZFYVE9	psi-mi:“MI:0407”(direct interaction)	0.540
ZFYVE9	RHO	psi-mi:“MI:0915”(physical association)	0.540
EEA1	ZFYVE9	psi-mi:“MI:0403”(colocalization)	0.450
RHO	ZFYVE9	psi-mi:“MI:0915”(physical association)	0.370
RHO	CD79A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): RHO (Reconstituted Complex), RHO (Two-hybrid), RHO (Reconstituted Complex), RHO (Reconstituted Complex), RHO (Biochemical Activity), RHO (Reconstituted Complex), RHO (Biochemical Activity), RHO (FRET), DNAJB2 (Co-localization), DNAJB2 (Affinity Capture-Western), RHO (Affinity Capture-Luminescence), HSPA4 (Affinity Capture-Western), RHO (Affinity Capture-Western), RHO (Reconstituted Complex)

ESM2 similar proteins: O13227, O42604, O62791, O62792, O62793, O62794, O62795, O62796, O62798, P02699, P02700, P08100, P15409, P28681, P29403, P31355, P32308, P35359, P51470, P51489, P52202, P56514, P56515, P56516, P79756, P79808, P79809, P79812, P79848, P79898, P79901, P79902, P79903, P79911, P87369, Q28886, Q68J47, Q6W3E1, Q769E8, Q8HY69

Diamond homologs: O12948, O13018, O13092, O18766, O18910, O18911, O18912, O18913, O18914, O35476, O35478, O35599, O42266, O42490, O42604, O57605, O62791, O62792, O62793, O62794, O62795, O62796, O93441, O93459, P02699, P02700, P03999, P04000, P04001, P08100, P0DN77, P0DN78, P22328, P22329, P22330, P22331, P22332, P22671, P28682, P28683

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
SP4	“up-regulates quantity by expression”	RHO	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	RHO	“transcriptional regulation”
KLF15	“down-regulates quantity by repression”	RHO	“transcriptional regulation”
NRL	“down-regulates quantity by repression”	RHO	“transcriptional regulation”
CRX	“down-regulates quantity by repression”	RHO	“transcriptional regulation”
RHO	“up-regulates activity”	GNAT1	binding
PRKCA	unknown	RHO	phosphorylation
GRK1	“up-regulates activity”	RHO	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	86
Likely pathogenic	63
Uncertain significance	267
Likely benign	117
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1038982	NM_000539.3(RHO):c.545G>A (p.Gly182Asp)	Pathogenic
1070044	NM_000539.3(RHO):c.1039C>A (p.Pro347Thr)	Pathogenic
1070456	NM_000539.3(RHO):c.180C>G (p.Tyr60Ter)	Pathogenic
1071997	NM_000539.3(RHO):c.545G>T (p.Gly182Val)	Pathogenic
1275786	NM_000539.3(RHO):c.196A>T (p.Lys66Ter)	Pathogenic
1284434	NM_000539.3(RHO):c.84G>T (p.Gln28His)	Pathogenic
13013	NM_000539.3(RHO):c.68C>A (p.Pro23His)	Pathogenic
13015	NM_000539.3(RHO):c.1039C>T (p.Pro347Ser)	Pathogenic
13018	NM_000539.3(RHO):c.50C>T (p.Thr17Met)	Pathogenic
13021	NM_000539.3(RHO):c.266G>A (p.Gly89Asp)	Pathogenic
13024	NM_000539.3(RHO):c.404G>T (p.Arg135Leu)	Pathogenic
13028	NM_000539.3(RHO):c.403C>T (p.Arg135Trp)	Pathogenic
13029	NM_000539.3(RHO):c.1030C>T (p.Gln344Ter)	Pathogenic
13030	NM_000539.3(RHO):c.886A>G (p.Lys296Glu)	Pathogenic
13032	NM_000539.3(RHO):c.1040C>G (p.Pro347Arg)	Pathogenic
13033	NM_000539.3(RHO):c.544G>A (p.Gly182Ser)	Pathogenic
13034	NM_000539.3(RHO):c.800C>T (p.Pro267Leu)	Pathogenic
13035	NM_000539.3(RHO):c.329G>A (p.Cys110Tyr)	Pathogenic
13037	NM_000539.3(RHO):c.158C>G (p.Pro53Arg)	Pathogenic
13040	NM_000539.3(RHO):c.568G>T (p.Asp190Tyr)	Pathogenic
13043	NM_000539.3(RHO):c.620T>G (p.Met207Arg)	Pathogenic
13044	NM_000539.3(RHO):c.875C>A (p.Ala292Glu)	Pathogenic
13045	NM_000539.3(RHO):c.269G>A (p.Gly90Asp)	Pathogenic
13047	NM_000539.3(RHO):c.151G>C (p.Gly51Arg)	Pathogenic
13048	NM_000539.3(RHO):c.341G>A (p.Gly114Asp)	Pathogenic
13049	NM_000539.3(RHO):c.491C>A (p.Ala164Glu)	Pathogenic
13050	NM_000539.3(RHO):c.511C>T (p.Pro171Ser)	Pathogenic
13052	NM_000539.3(RHO):c.1033G>C (p.Val345Leu)	Pathogenic
13053	NM_000539.3(RHO):c.1040C>A (p.Pro347Gln)	Pathogenic
13055	NM_000539.3(RHO):c.67C>G (p.Pro23Ala)	Pathogenic

SpliceAI

596 predictions. Top by Δscore:

Variant	Effect	Δscore
3:129529059:G:GT	donor_gain	1.0000
3:129529070:G:GT	donor_gain	1.0000
3:129529090:GGGCG:G	donor_gain	1.0000
3:129529091:GGCGG:G	donor_gain	1.0000
3:129530870:TTGCA:T	acceptor_loss	1.0000
3:129530871:TGCA:T	acceptor_loss	1.0000
3:129530872:GCA:G	acceptor_loss	1.0000
3:129530873:CAGGT:C	acceptor_loss	1.0000
3:129530874:A:AC	acceptor_loss	1.0000
3:129530874:A:AG	acceptor_gain	1.0000
3:129530874:AGGT:A	acceptor_gain	1.0000
3:129530875:G:GC	acceptor_loss	1.0000
3:129530875:G:GG	acceptor_gain	1.0000
3:129530875:GGTG:G	acceptor_gain	1.0000
3:129531041:CCAGG:C	donor_loss	1.0000
3:129531042:CAGGT:C	donor_loss	1.0000
3:129531043:AGGTA:A	donor_loss	1.0000
3:129531044:GGTAA:G	donor_loss	1.0000
3:129531045:GTAAT:G	donor_loss	1.0000
3:129531046:T:G	donor_loss	1.0000
3:129532413:GGAG:G	donor_gain	1.0000
3:129532414:GAGG:G	donor_gain	1.0000
3:129532768:AGCAG:A	donor_loss	1.0000
3:129532770:CAG:C	donor_loss	1.0000
3:129532772:GGTG:G	donor_loss	1.0000
3:129532774:T:G	donor_loss	1.0000
3:129533602:TTCCA:T	acceptor_loss	1.0000
3:129533603:TCCAG:T	acceptor_loss	1.0000
3:129533604:CCAGT:C	acceptor_loss	1.0000
3:129533605:CAGTT:C	acceptor_loss	1.0000

AlphaMissense

2300 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:129528967:C:A	N78K	0.999
3:129528967:C:G	N78K	0.999
3:129528969:T:C	L79P	0.999
3:129530906:T:C	L131P	0.999
3:129530918:G:C	R135P	0.999
3:129530995:T:A	W161R	0.999
3:129530995:T:C	W161R	0.999
3:129531037:T:A	W175R	0.999
3:129531037:T:C	W175R	0.999
3:129532364:C:A	P215H	0.999
3:129532364:C:G	P215R	0.999
3:129532397:T:C	L226P	0.999
3:129532617:T:C	F261L	0.999
3:129532619:C:A	F261L	0.999
3:129532619:C:G	F261L	0.999
3:129532629:T:A	W265R	0.999
3:129532629:T:C	W265R	0.999
3:129532724:G:C	K296N	0.999
3:129532724:G:T	K296N	0.999
3:129533608:T:C	F313L	0.999
3:129533609:T:C	F313S	0.999
3:129533609:T:G	F313C	0.999
3:129533610:C:A	F313L	0.999
3:129533610:C:G	F313L	0.999
3:129533612:G:C	R314P	0.999
3:129528884:G:C	G51R	0.998
3:129528898:C:A	N55K	0.998
3:129528898:C:G	N55K	0.998
3:129528939:G:C	R69P	0.998
3:129528960:T:A	L76Q	0.998

dbSNP variants (sampled 300 via entrez): RS1000029963 (3:129533528 C>A,T), RS1000193322 (3:129531753 A>G), RS1000346661 (3:129528115 G>T), RS1000374041 (3:129528582 A>T), RS1000532131 (3:129533034 G>A), RS1000756559 (3:129526648 T>A), RS1001505294 (3:129535198 C>G), RS1001583714 (3:129532333 A>G,T), RS1001703259 (3:129534807 A>G), RS1001833805 (3:129527098 T>C), RS1001866562 (3:129527857 C>T), RS1003128409 (3:129532186 C>T), RS1003329675 (3:129534812 C>G,T), RS1003611523 (3:129534986 C>T), RS1003947341 (3:129529217 C>T)

Disease associations

OMIM: gene MIM:180380 | disease phenotypes: MIM:613731, MIM:268000, MIM:136880, MIM:610445, MIM:617090, MIM:204000, MIM:120970, MIM:116200, MIM:180050, MIM:312530, MIM:300216, MIM:618184, MIM:602093, MIM:310500, MIM:613587, MIM:248200

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 4	Definitive	Semidominant
congenital stationary night blindness autosomal dominant 1	Definitive	Autosomal dominant
congenital stationary night blindness	Supportive	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant
fundus albipunctatus	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
RHO-related retinopathy	Definitive	SD

Mondo (23): inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa 4 (MONDO:0013395), retinitis pigmentosa (MONDO:0019200), fundus albipunctatus (MONDO:0007639), congenital stationary night blindness autosomal dominant 1 (MONDO:0012498), night blindness (MONDO:0004588), retinal disorder (MONDO:0005283), microcephaly 17, primary, autosomal recessive (MONDO:0014908), retinitis punctata albescens (MONDO:0018877), optic atrophy (MONDO:0003608), Leber congenital amaurosis (MONDO:0018998), cone-rod dystrophy (MONDO:0015993), optic disk drusen (MONDO:0001746), blindness (disorder) (MONDO:0001941), pathologic nystagmus (MONDO:0004843)

Orphanet (12): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791), Congenital stationary night blindness (Orphanet:215), Fundus albipunctatus (Orphanet:227796), Retinitis punctata albescens (Orphanet:52427), Autosomal recessive primary microcephaly (Orphanet:2512), Leber congenital amaurosis (Orphanet:65), Cone rod dystrophy (Orphanet:1872), Coats disease (Orphanet:190), Occult macular dystrophy (Orphanet:247834), Severe early-childhood-onset retinal dystrophy (Orphanet:364055), Stargardt disease (Orphanet:827)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000580	Pigmentary retinopathy
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000654	Decreased light- and dark-adapted electroretinogram amplitude
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001123	Visual field defect
HP:0001142	Lenticonus

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002875_143	Diisocyanate-induced asthma	3.000000e-06
GCST005956_82	Waist-to-hip ratio adjusted for BMI	2.000000e-07
GCST005958_5	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-10
GCST005962_16	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-11
GCST012354_1	Anxiety	8.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009863	anxiety measurement

MeSH disease descriptors (17)

Descriptor	Name	Tree numbers
D001766	Blindness	C10.597.751.941.162; C11.966.075; C23.888.592.763.941.162
D002386	Cataract	C11.510.245
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D009755	Night Blindness	C11.966.671
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D015594	Optic Disk Drusen	C10.292.700.450; C11.640.513
D012163	Retinal Detachment	C11.768.648
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D058456	Retinal Telangiectasis	C11.768.748; C14.907.823.502
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C562733	Fundus Albipunctatus (supp.)
C566474	Night Blindness, Congenital Stationary, Autosomal Dominant 1 (supp.)
C536122	Night blindness, congenital stationary (supp.)
C566706	Retinitis Pigmentosa 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296308 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Opsin receptors

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
fasudil	decreases reaction, increases expression	2
bisphenol A	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
diethyl maleate	increases expression	1
alkannin	decreases reaction, increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
lipopolysaccharide, Escherichia coli O111 B4	decreases reaction, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Carcinogens	increases expression	1
Dexamethasone	increases expression, decreases reaction	1
Estradiol	decreases expression	1
Methapyrilene	decreases methylation	1
Mutagens	increases expression	1
Paraquat	decreases reaction, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Potassium Chloride	decreases response to substance, increases expression	1
Dronabinol	decreases response to substance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Lactic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1251195	Binding	Induction of subcellular localization of HA-tagged human rhodopsin P23H mutant on HEK293 cell surface by immunofluorescence microscopy	Retinobenzaldehydes as proper-trafficking inducers of folding-defective P23H rhodopsin mutant responsible for retinitis pigmentosa. — Bioorg Med Chem

Cellosaurus cell lines

15 cell lines: 11 induced pluripotent stem cell, 2 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_AM53	GM11031	Transformed cell line	Female
CVCL_AM54	GM11105	Transformed cell line	Male
CVCL_B5FX	SYSUSCi001-A	Induced pluripotent stem cell	Male
CVCL_E5FV	HeLa RHO	Cancer cell line	Female
CVCL_E5FW	HeLa RHO P347S	Cancer cell line	Female
CVCL_QX16	59SCV3	Induced pluripotent stem cell	Male
CVCL_QX17	59SV3	Induced pluripotent stem cell	Male
CVCL_QX18	59SV4	Induced pluripotent stem cell	Male
CVCL_QX19	59SV9	Induced pluripotent stem cell	Male
CVCL_QX67	P59M9	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

259 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