RBP4
protein-codingretinol binding protein 4, the group of Lipocalins
Gene summary
This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A alcohol) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014060
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014635
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014060
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016764
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014060
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0000170
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014060
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014635
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014635
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014060
Submitter: ClinGen
The *RBP4* gene was first reported in relation to ocular disease in 1999, in affected members from a family with autosomal recessive inheritance who were diagnosed with retinal dystrophy and showed iris coloboma and comedogenic acne (Seeliger et al., PMID: 9888420). Affected individuals generally exhibit retinal features including night blindness, progressive loss of visual acuity, peripheral visual field constriction, reduced or absent rod and reduced cone electroretinogram responses, white dots in the fundus, retinal pigment epithelium atrophy, and/or retinal blood vessel attenuation. These are accompanied in some cases by the presence of colobomas and/or comedonal acne that may be severe or extend into later adulthood. Some cases have been reported with rheumatoid arthritis (PMID: 36317196) or osteoarthritis (PMID: 23189188), which could potentially be part of the spectrum of disease. Circulating retinol and retinol binding protein are generally reduced or undetectable. Families were subsequently identified with microphthalmia, clinical anophthalmia, and/or coloboma in the absence of retinal involvement, showing autosomal dominant inheritance with incomplete penetrance and a parent of origin effect in which maternal genotype and dietary vitamin A during pregnancy influenced the expressivity of the phenotype (PMID: 25910211). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the biallelic and monoallelic cases were distinguishable not only by their mode of inheritance, but by the presence or absence of retinal features, and by the underlying molecular mechanism (loss-of-function vs. dominant negative variants). Therefore, cases caused by inherited *RBP4* variants have been split into two separate disease entities, with the present curation focusing on autosomal recessive cases referred to as *RBP4*-related recessive retinopathy with or without ocular malformation and acne vulgaris. Seven suspected disease-causing variants were scored as part of this curation (two missense, two nonsense, and three disrupting canonical splice sites). These variants have been collectively reported in six probands in six publications (PMID: 9888420, PMID: 23189188, PMID: 28041643, PMID: 32323592, PMID: 36317196, and PMID: 35743034). The variant types and functional studies of disease-causing missense variants (PMID: 9888420) 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 *RBP4* encodes a retinol binding protein that is secreted from hepatocytes into the bloodstream in a complex with transthyretin to deliver retinol to target cells (PMID: 35334893), including photoreceptor cells in the retina. *RBP4* shows high expression in the liver as well as in adipose tissue, breast, and retinal pigment epithelium (PMID: 30239781). Mice with homozygous knockout of *Rbp4* exons 1 and 2 show impaired dark-adapted electroretinogram responses and reduced retinol levels (PMID: 10469643), recapitulating the molecular features and impaired retinal function of the human patients. These defects could be rescued by transgenic overexpression of human *RBP4* (PMID: 10469643). In summary, *RBP4* has a Definitive association with *RBP4*-related recessive retinopathy with or without ocular malformation and acne vulgaris. 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 March 5th, 2026 (SOP Version 12).
Inheritance Pattern: AR
Disease ID:MONDO:0014060
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0000170
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; 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: It has been suggested that high-dose vitamin A supplementation may be beneficial in Retinol dystrophy, iris coloboma, and comedogenic acne syndrome
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RBP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006744.4. 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 | 48 | 1 | 50 | ||
| missense | 1 | 10 | 91 | 7 | 109 | |
| nonsense | 4 | 1 | 5 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | 1 | 3 | ||
| splice donor/acceptor (+/-2bp) | 3 | 4 | 7 | |||
| Total | 9 | 15 | 95 | 55 | 1 | 175 |
Highest pathogenic variant AF is 0.000032871845
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006735.2 | 5 | MANE Select | |
| Ensembl | ENSP00000360519.3 | 5 | MANE Select | |
| RefSeq | NP_001310446.1 | 5 | Standard | |
| RefSeq | NP_001310447.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| rbp4 | Danio rerio | Structure: post-vent region Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Sterol Regulatory Element-Binding Proteins (SREBP) signalling
- Vitamin A and Carotenoid Metabolism
- Signaling by GPCR
- Signal Transduction
- Metabolism of fat-soluble vitamins
Biological Process
- retinoid metabolic process
- eye development
- gluconeogenesis
- heart development
- visual perception
Molecular Function
- protein binding
- retinal binding
- retinol binding
- retinol transmembrane transporter activity
- protein heterodimerization activity
Cellular Component
- extracellular region
- extracellular space
- cytosol
- protein-containing complex
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371467
- Coding exons
- 5
- Length
- 10058
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125742
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.775 | 98 | 122 | 0.803 | 0.00000758 | 1316 |
| Missense (PolyPhen) | 35 | 51.766 | 0.67611 | 561 | ||
| Synonymous | 0.000807 | 55 | 55.0 | 1.00 | 0.00000390 | 377 |
| Loss of Function | 2.45 | 2 | 10.6 | 0.189 | 5.07e-7 | 110 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Retinol-binding protein that mediates retinol transport in blood plasma (PubMed:5541771). Delivers retinol from the liver stores to the peripheral tissues (Probable). Transfers the bound all-trans retinol to STRA6, that then facilitates retinol transport across the cell membrane (PubMed:22665496). {ECO:0000269|PubMed:22665496, ECO:0000305, ECO:0000305|PubMed:5541771}.;
- Disease
- DISEASE: Retinal dystrophy, iris coloboma, and comedogenic acne syndrome (RDCCAS) [MIM:615147]: A disease characterized by retinal degeneration, ocular colobomas involving both the anterior and posterior segment, impaired night vision and loss of visual acuity. Additional characteristic features include developmental abnormalities and severe acne. {ECO:0000269|PubMed:10232633, ECO:0000269|PubMed:23189188, ECO:0000269|PubMed:9888420}. Note=The disease is caused by mutations affecting the gene represented in this entry. Loss of functional RBP4 protein results in serum retinol deficiency. Lack of normal levels of retinol impairs the visual cycle leading to night blindness at early stages; prolonged deficiency may lead to retinal degeneration. Additionally, retinol deficiency may result in dry skin, increased susceptibility to infection and acne (PubMed:23189188). {ECO:0000269|PubMed:23189188}.; DISEASE: Microphthalmia, isolated, with coloboma, 10 (MCOPCB10) [MIM:616428]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:25910211}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.159
- RVIS EVS
- -0.47
- RVIS percentile EVS
- 23.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.928
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |