RPE65
Chr 1ARADretinoid isomerohydrolase RPE65
Also known as: BCO3, LCA2, RP20, mRPE65, p63, rd12, sRPE65
RPE65 encodes a critical isomerohydrolase that catalyzes the essential conversion of all-trans-retinyl esters to 11-cis-retinol in the retinal visual cycle, regenerating the chromophore needed for both rod and cone photoreceptors. Mutations cause early-onset severe blinding disorders including Leber congenital amaurosis and retinitis pigmentosa with or without choroidal involvement, inherited in autosomal recessive or autosomal dominant patterns. The gene shows very high intolerance to loss-of-function variants (pLI near 1), reflecting its essential role in vision.
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
599 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 37 | 8 | 32 | 0 | 77 |
Likely Pathogenic | 26 | 22 | 9 | 0 | 57 |
VUS | 2 | 177 | 14 | 8 | 201 |
Likely Benign | 1 | 5 | 127 | 124 | 257 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 3 | |||
| Total | 66 | 212 | 183 | 132 | 596 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
RPE65 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Gene Therapy in Subjects With Biallelic RPE65 Mutation-associated Retinal Dystrophy
RECRUITINGSafety and Efficacy Study in Subjects With Leber Congenital Amaurosis
ACTIVE NOT RECRUITINGPhase I Trial of Gene Vector to Patients With Retinal Disease Due to RPE65 Mutations
ACTIVE NOT RECRUITINGSafety and Efficacy Trial of HG004 for Leber Congenital Amaurosis Related to Rpe65 Gene Mutations (STAR)
RECRUITINGEfficacy and Safety of LX101 for Inherited Retinal Dystrophy Associated With RPE65 Mutations
ACTIVE NOT RECRUITINGInherited Retinal Diseases: Natural History and Genotype-Phenotype Correlations
NOT YET RECRUITINGStudy of Efficacy and Safety of Voretigene Neparvovec in Japanese Patients With Biallelic RPE65 Mutation-associated Retinal Dystrophy
ACTIVE NOT RECRUITINGAn Expanded Clinical Study Evaluating the AAV2-RPE65 Gene Therapy(LX101) in Patients With LCA
NOT YET RECRUITINGPhase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2
ACTIVE NOT RECRUITINGLeber Congenital Amaurosis Inherited Blindness of Gene Therapy Trial(LIGHT)
ACTIVE NOT RECRUITINGSafety and Tolerability of LX101 for Inherited Retinal Dystrophy Associated With RPE65 Mutations
ACTIVE NOT RECRUITINGLong-term Follow-up Study in Subjects Who Received Voretigene Neparvovec-rzyl (AAV2-hRPE65v2)
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools