RBP3
protein-codingretinol binding protein 3
Gene summary
Interphotoreceptor retinol-binding protein is a large glycoprotein known to bind retinoids and found primarily in the interphotoreceptor matrix of the retina between the retinal pigment epithelium and the photoreceptor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a critical role in the visual process.The human IRBP gene is approximately 9.5 kbp in length and consists of four exons separated by three introns. The introns are 1.6-1.9 kbp long. The gene is transcribed by photoreceptor and retinoblastoma cells into an approximately 4.3-kilobase mRNA that is translated and processed into a glycosylated protein of 135,000 Da. The amino acid sequence of human IRBP can be divided into four contiguous homology domains with 33-38% identity, suggesting a series of gene duplication events. In the gene, the boundaries of these domains are not defined by exon-intron junctions, as might have been expected. The first three homology domains and part of the fourth are all encoded by the first large exon, which is 3,180 base pairs long. The remainder of the fourth domain is encoded in the last three exons, which are 191, 143, and approximately 740 base pairs long, respectively. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014093
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019118
Submitter: ClinGen
The *RBP3* gene was first reported in relation to retinal disease in 2009, in affected members from a family with autosomal recessive inheritance who were diagnosed with retinitis pigmentosa as adults (den Hollander et al., PMID: 19074801). Subsequent studies expanded the spectrum of disease to include individuals diagnosed with high myopia and retina dystrophy in childhood (PMID: 25766589). Affected individuals generally exhibit progressive loss of visual acuity, high myopia, tessellated fundus, night blindness, peripheral visual field constriction, reduced electroretinogram amplitudes from rods and/or cones, optical coherence tomography showing retinal thinning, pigmentary retinopathy with attenuation of retinal blood vessels, and/or cataracts. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the diverse cases shared similarities in their retinal features, mode of inheritance (autosomal recessive), and underlying molecular mechanism (biallelic loss-of-function). Therefore, cases caused by inherited RBP3 variants have been lumped into a single gene curation focusing on a disease entity referred to as *RBP3*-related retinopathy. Nine suspected disease-causing variants were scored as part of this curation (one missense, seven nonsense, and one frameshift). These variants have been collectively reported in eight probands in four publications (PMID: 19074801, PMID: 25766589, PMID: 37806543, PMID: 40895869). The variant types and functional studies of disease-causing missense variants (PMID: 23486466) indicate that the mechanism of pathogenicity is biallelic loss-of-function. The reported families had relatively small numbers of affected individuals, so segregation evidence did not contribute to the scoring of the gene-disease relationship. This gene-disease association is also supported by biochemical evidence that *RBP3* encodes an interphotoreceptor retinoid-binding protein that facilitates the transfer of retinoids in the visual cycle, helps to transport lipids between the RPE and photoreceptors, and has a thiol-dependent antioxidant activity that maintains the balance between reduction and oxidation in the retina (PMID: 33328889). *RBP3* shows highly specific expression in the retina and retinal pigment epithelium (PMID: 30239781). Mice with homozygous knockout of the *Irbp* exon 1 and promoter show slowly progressive loss of photoreceptor nuclei and changes in the structural integrity of the receptor outer segments on histological exam (PMID: 10508404, PMID: 10750831) accompanied by histological confirmation of apoptosis (PMID: 21642628) and loss of rod and cone electroretinogram amplitude relative to wild-type and heterozygous controls (PMID: 9614228, PMID: 10750831). Partial coherence interferometry and photorefraction studies showed the mice increasingly become myopic (PMID: 21642628), despite minor defects in visual cycle kinetics including recovery of 11-cis-retinal and regeneration of rhodopsin (PMID: 10508404, PMID: 10750831). In summary, *RBP3* has a Definitive association with *RBP3*-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on May 20th, 2026 (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014093
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014093
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014093
Submitter: LiferaOmics
Genetic evidence – Published PMID: 19074801 – Family 1 – one proband (affected siblings counted under segregation). Case-level (biallelic non-LOF in AR model; homozygous; consanguinity) = 0.1; Segregation (multiple affected siblings; conservative assignment) = 0.1; Case-control = 0 Family 1 total = 0.1 PMID: 40895869 – Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity unknown → no deduction applied) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 1.5 PMID: 23105016 – Family 3 – one proband Case-level (AR homozygous truncating/predicted LoF;) = 1.5 Segregation = 0 (limited segregation data reported in summary) Case-control = 0 Family 3 total = 1.5 PMID: 25766589: Two independent families each scored independently Case-level (AR homozygous nonsense; predicted null; consanguineous) = 1.0 Segregation = 1 Case-control = 0 Each family score= 2.0 PMID: 25766589 Total=4 Published genetic evidence total = 7.1 / 12 Genetic evidence – Our cases Family 1-One proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Family 2-One proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity unknown → no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 1.5 Our cases total = 2.5 / 12 Total genetic evidence (published AR + our cases) Published genetic evidence: 7.1 Our additional cases: 2.5 Total genetic evidence = 9.6 / 12 Experimental evidence – Published PMID: 9614228 – Non-human model organism (Rbp3 knockout mouse with photoreceptor degeneration) = 2.0 PMID: 23486466 – Functional alteration (non-patient cells; RP-associated IRBP variant causes secretory defect and cytotoxicity) = 0.5 Gene function / biological plausibility (IRBP essential for retinoid transport; disruption consistent with rod–cone degeneration) = 0.5 Experimental evidence total = 3.0 / 6 Overall score Genetic evidence =9.6 Experimental evidence = 3.0 Overall score = 12.6 / 18
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RBP3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002900.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 6 | 371 | 3 | 381 | |
| missense | 1 | 7 | 686 | 46 | 3 | 743 |
| nonsense | 14 | 7 | 3 | 24 | ||
| start loss | 1 | 1 | ||||
| frameshift | 8 | 14 | 2 | 24 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 23 | 30 | 699 | 417 | 6 | 1175 |
Highest pathogenic variant AF is 0.000029765079
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002891.1 | 4 | MANE Select | |
| Ensembl | ENSP00000463151.1 | 4 | MANE Select |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- the visual cycle I (vertebrates)
Biological Process
- retinoid metabolic process
- proteolysis
- lipid metabolic process
- visual perception
Molecular Function
- retinoid binding
- serine-type peptidase activity
- retinal binding
- retinol binding
Cellular Component
- extracellular region
- extracellular space
- cone matrix sheath
- extracellular vesicle
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: IRBP shuttles 11-cis and all trans retinoids between the retinol isomerase in the pigment epithelium and the visual pigments in the photoreceptor cells of the retina.;
- Disease
- DISEASE: Retinitis pigmentosa 66 (RP66) [MIM:615233]: 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:19074801, ECO:0000269|PubMed:23486466}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.256
Intolerance Scores
- LoFtool
- 0.478
- RVIS EVS
- -0.96
- RVIS percentile EVS
- 9.02
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.344
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |