RPE65

Chr 1ARAD

retinoid isomerohydrolase RPE65

Also known as: BCO3, LCA2, RP20, mRPE65, p63, rd12, sRPE65

NCBI Gene: 6121 ENSG00000116745 UniProt: Q16518 OMIM: 180069

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a component of the vitamin A visual cycle of the retina which supplies the 11-cis retinal chromophore of the photoreceptors opsin visual pigments. It is a member of the carotenoid cleavage oxygenase superfamily. All members of this superfamily are non-heme iron oxygenases with a seven-bladed propeller fold and oxidatively cleave carotenoid carbon:carbon double bonds. However, the protein encoded by this gene has acquired a divergent function that involves the concerted O-alkyl ester cleavage of its all-trans retinyl ester substrate and all-trans to 11-cis double bond isomerization of the retinyl moiety. As such, it performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Mutations in this gene are associated with early-onset severe blinding disorders such as Leber congenital. [provided by RefSeq, Oct 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Leber congenital amaurosis 2MIM #204100

Retinitis pigmentosa 20MIM #613794

Retinitis pigmentosa 87 with choroidal involvementMIM #618697

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.11

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — RPE65

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.11LOEUF

pLI 0.000

Z-score 1.07

OE 0.79 (0.57–1.11)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.24Z-score

OE missense 1.04 (0.94–1.15)

284 obs / 272.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.79 (0.57–1.11)

0≤0.351.4

Missense OE?1.04 (0.94–1.15)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 24 / 30.4Missense obs/exp: 284 / 272.8Syn Z: -1.54

Background carrier burden — how many people carry a rare variant somewhere in RPE65?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

697 rare PASS variants

Rare truncating (LoF)

1 in 1,300

108 rare PASS variants

Rare synonymous (reference)

1 in 77

241 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RPE65. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 1,500
South Asian	~43k	1 in 84	1 in 2,400
Remaining (unassigned)	~30k	1 in 81	1 in 1,400
European (Finnish)	~27k	1 in 360	1 in 950
Admixed American	~22k	1 in 72	1 in 680
African / African American	~21k	1 in 87	1 in 630
East Asian	~20k	1 in 96	1 in 740
Ashkenazi Jewish	~13k	1 in 1,200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 97	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓