PRPH2

Chr 6ADARDigenic dominant

peripherin 2

Also known as: AOFMD, AVMD, CACD2, DS, MDBS1, RDS, RP7, TSPAN22

NCBI Gene: 5961 ENSG00000112619 UniProt: P23942 OMIM: 179605

The protein is essential for photoreceptor outer segment disk morphogenesis and maintenance of disk structure in both rod and cone cells of the retina. Mutations cause a spectrum of retinal dystrophies including retinitis pigmentosa, Leber congenital amaurosis, macular dystrophies, and choroidal dystrophy, with onset ranging from congenital to adult depending on the specific condition. Inheritance patterns include autosomal dominant, autosomal recessive, and digenic forms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis. Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/AR/Digenic dominantLOEUF 0.676 OMIM phenotypes

Clinical Summary— PRPH2

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Gene-Disease Validity (ClinGen)

PRPH2-related retinopathy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.116

Z-score 2.44

OE 0.29 (0.14–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.10Z-score

OE missense 0.98 (0.87–1.10)

189 obs / 193.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.67)

0≤0.351.4

Missense OE?0.98 (0.87–1.10)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 4 / 13.8Missense obs/exp: 189 / 193.0Syn Z: -0.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePRPH2-related macular dystrophyOTHERAD

definitivePRPH2-related retinitis pigmentosaOTHERAR

definitivePRPH2-related Leber congenital amaurosisLOFAR

This gene — mechanism propensity

0.75top 25%

GOF

0.75top 25%

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

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

DNFunctional, structural and biochemical analyses showed that, while R172W P/rds is appropriately localized, a direct correlation exists between transgene expression levels and the onset/severity of the phenotype. In the wild-type background, both cone and rod photoreceptors' structure and function we1

GOFIn humans, gain-of-function mutations in PRPH2 result in both autosomal dominant retinitis pigmentosa and dominant maculopathies.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References