GeneBe

RHO

protein-coding

rhodopsin, the group of Opsin receptors

Gene summary

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. [provided by RefSeq, Aug 2017]

Previous symbols:
  • RP4

MANE transcript

NM_000539.3

Inheritance

AD, AR, SD

ClinVar variants

P:237U:244B:121

Top phenotype

Retinitis pigmentosa 4; Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr3:129,528,639-129,535,344

External References & Databases

Ensembl (ENSG00000163914)NCBI Gene (6010)OMIM (180380)HGNC:10012GenCCUniProt (P08100)AlphaFoldClinVar (RHO)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~6.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013395

Submitter: G2P

retinitis pigmentosa 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013395

Submitter: Labcorp Genetics (formerly Invitae)

congenital stationary night blindness autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012498

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

retinitis pigmentosa 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013395

Submitter: G2P

congenital stationary night blindness autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012498

Submitter: PanelApp Australia

RHO-related retinopathyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0700380

Submitter: ClinGen

*RHO* was first reported in relation to autosomal dominant retinitis pigmentosa in 1990 (Dryja et al., PMID: 2137202), *RHO* variants have also been reported as the cause of autosomal recessive retinitis pigmentosa (PMID: 7987385) and autosomal dominant congenital stationary night blindness (PMID: 8107847). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found diverse molecular mechanisms underlying these disease entities, ranging from biallelic loss-of-function to monoallelic gain-of-function, but no significant phenotypic variability as well as some overlap in inheritance pattern among the different groups of affected patients. Therefore, retinitis pigmentosa 4 (MIM# 613731) and autosomal dominant congenital stationary night blindness 1 (MIM# 610445) have been lumped into a single curation, under the broad disease term *RHO*-related retinopathy. This curation includes 6 variants (5 missense and 1 nonsense) that have been reported in 5 probands in 6 publications (PMIDs: 1302614, 2137202, 26202387, 7846071, 38111930, 31239368, 34635090). More evidence is available in the literature, but was not required for inclusion. The mechanism of pathogenicity is reported to be mainly gain-of-function or dominant negative, with a few cases being loss-of-function. This gene-disease relationship is also supported by animal models, expression studies and *in vitro* functional assays (PMIDs: 38479725, 30976840, 17167410, 21126223, 30239781). In summary, there is definitive evidence supporting the relationship between *RHO* and *RHO*-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the ClinGen Retina GCEP on January, 2nd, 2025 (SOP Version 11).

retinitis pigmentosa 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013395

Submitter: PanelApp Australia

retinitis pigmentosa 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013395

Submitter: PanelApp Australia

fundus albipunctatusLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007639

Submitter: Labcorp Genetics (formerly Invitae)

congenital stationary night blindness autosomal dominant 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012498

Submitter: G2P

retinitis pigmentosa 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013395

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 4DEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0013395

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Retinitis pigmentosa 4; Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1AD/AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Oral vitamin A may slow retinal degeneration in some forms of retinitis pigmentosa

Refs: 2613244; 2137202; 2215617; 2333895; 1882937; 1302614; 1301135; 8512476; 8358437; 7846071; 8841304; 9197578; 9888392; 10980774; 20301590; 20555336; 21174529; 22419850Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RHO variants in ClinVar

38 Conditions Cataloged
not providedTotal: 543
RHO-related disorderTotal: 181
Retinitis pigmentosa 4Total: 130
Retinal dystrophyTotal: 108
not specifiedTotal: 72
Retinitis pigmentosaTotal: 70
Congenital stationary night blindness autosomal dominant 1Total: 46
Retinal disorderTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000539.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
8
clinvar
103
clinvar
1
clinvar
 112
missense
53
clinvar
121
clinvar
230
clinvar
16
clinvar
1
clinvar
 421
nonsense
9
clinvar
15
clinvar
 24
start loss
1
clinvar
 1
frameshift
10
clinvar
16
clinvar
5
clinvar
 31
splice donor/acceptor (+/-2bp)
3
clinvar
10
clinvar
 13
Total751622441192602

Highest pathogenic variant AF is 0.00008797679

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000539.3RefSeqNP_000530.15MANE Select
ENST00000296271.4EnsemblENSP00000296271.35MANE Select
ENST00001140026.1EnsemblENSP00000805096.15Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
rhoDanio rerio

Structure: retinal rod cell

Quality: decreased thickness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Phototransduction - Homo sapiens (human)
  • Integrated Breast Cancer Pathway
  • Integrin-mediated Cell Adhesion
  • Regulation of Microtubule Cytoskeleton
  • GPCRs, Class A Rhodopsin-like

Biological Process

  • retinoid metabolic process
  • protein phosphorylation
  • G protein-coupled receptor signaling pathway
  • visual perception
  • phototransduction

Molecular Function

  • G protein-coupled receptor activity
  • 11-cis retinal binding
  • protein binding
  • G protein-coupled photoreceptor activity
  • metal ion binding

Cellular Component

  • Golgi membrane
  • photoreceptor outer segment
  • photoreceptor inner segment
  • Golgi apparatus
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000296271
Coding exons
5
Length
6530
Individuals with no LoFs
125727
Homozygous LoFs
0
Heterozygous LoFs
21
Defined
125748
p
0.0000835
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2422092190.9540.00001512293
Missense (PolyPhen)122123.40.988641300
Synonymous-1.3511396.21.170.00000815697
Loss of Function1.35813.30.6005.87e-7150

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.000140.00014rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Photoreceptor required for image-forming vision at low light intensity (PubMed:8107847, PubMed:7846071). Required for photoreceptor cell viability after birth (PubMed:2215617, PubMed:12566452). Light-induced isomerization of the chromophore 11-cis-retinal to all-trans-retinal triggers a conformational change that activates signaling via G-proteins (PubMed:8107847, PubMed:28524165, PubMed:26200343, PubMed:28753425). Subsequent receptor phosphorylation mediates displacement of the bound G- protein alpha subunit by the arrestin SAG and terminates signaling (PubMed:28524165, PubMed:26200343). {ECO:0000269|PubMed:12566452, ECO:0000269|PubMed:2215617, ECO:0000269|PubMed:26200343, ECO:0000269|PubMed:28753425, ECO:0000269|PubMed:7846071, ECO:0000269|PubMed:8107847, ECO:0000305|PubMed:28524165}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:12566452, ECO:0000269|PubMed:1302614, ECO:0000269|PubMed:1391967, ECO:0000269|PubMed:1833777, ECO:0000269|PubMed:1840561, ECO:0000269|PubMed:1862076, ECO:0000269|PubMed:1897520, ECO:0000269|PubMed:1985460, ECO:0000269|PubMed:19934218, ECO:0000269|PubMed:19960070, ECO:0000269|PubMed:2137202, ECO:0000269|PubMed:2215617, ECO:0000269|PubMed:22334370, ECO:0000269|PubMed:2239971, ECO:0000269|PubMed:7633434, ECO:0000269|PubMed:7981701, ECO:0000269|PubMed:7987326, ECO:0000269|PubMed:7987331, ECO:0000269|PubMed:8045708, ECO:0000269|PubMed:8076945, ECO:0000269|PubMed:8081400, ECO:0000269|PubMed:8088850, ECO:0000269|PubMed:8317502, ECO:0000269|PubMed:8353500, ECO:0000269|PubMed:8554077, ECO:0000269|PubMed:9452035}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:7846071, ECO:0000269|PubMed:8107847, ECO:0000269|PubMed:8358437, ECO:0000269|PubMed:9888392}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.833

Intolerance Scores

LoFtool
0.388
RVIS EVS
-0.89
RVIS percentile EVS
10.37

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.881

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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