Retinitis pigmentosa: genes and variants

Genes linked to Retinitis pigmentosa

• CRB1: Protein crumbs homolog 1

  It helps maintain apical polarity and structural organization of photoreceptors and Muller glia in the retina. Biallelic pathogenic variants cause inherited retinal dystrophies including Leber congenital amaurosis and retinitis pigmentosa.

  128 disease-causing and 493 uncertain variants in CRB1 are linked to Retinitis pigmentosa.

• RHO: Rhodopsin

  Photon absorption converts its retinal chromophore and triggers the G-protein cascade that initiates rod phototransduction. Pathogenic variants are a major cause of autosomal dominant retinitis pigmentosa and can also cause congenital stationary night blindness.

  65 disease-causing and 23 uncertain variants in RHO are linked to Retinitis pigmentosa.

• ABCA4: Retinal-specific phospholipid-transporting ATPase ABCA4

  It flips retinal-derived lipid adducts across photoreceptor disc membranes so they can be cleared during the visual cycle. Biallelic loss-of-function variants cause Stargardt disease and can also produce cone-rod dystrophy or retinitis pigmentosa.

  58 disease-causing and 35 uncertain variants in ABCA4 are linked to Retinitis pigmentosa.

• USH2A: Usherin

  It helps organize extracellular and membrane structures required for cochlear hair-cell and photoreceptor function. Biallelic pathogenic variants cause Usher syndrome type 2A or nonsyndromic retinitis pigmentosa and can also produce isolated hearing loss.

  23 disease-causing and 117 uncertain variants in USH2A are linked to Retinitis pigmentosa.

• RPE65: Retinoid isomerohydrolase

  It regenerates 11-cis-retinoid chromophore in the retinal pigment epithelium, allowing visual pigments to recover after light exposure. Biallelic loss-of-function variants cause severe inherited retinal dystrophy, and RPE65-associated disease is treatable with approved gene-replacement therapy.

  21 disease-causing and 187 uncertain variants in RPE65 are linked to Retinitis pigmentosa.

• PDE6B: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta

  It hydrolyzes cyclic GMP after light activation in rod photoreceptors, causing cyclic-nucleotide-gated channels to close and initiating the electrical visual response. Biallelic loss-of-function variants cause retinitis pigmentosa, while certain variants can cause congenital stationary night blindness.

  15 disease-causing and 64 uncertain variants in PDE6B are linked to Retinitis pigmentosa.

• PRPH2: Peripherin-2

  It organizes and stabilizes the rim structure of photoreceptor outer-segment discs. Pathogenic variants cause a wide range of inherited retinal diseases including retinitis pigmentosa, pattern dystrophy, and macular dystrophy.

  14 disease-causing and 15 uncertain variants in PRPH2 are linked to Retinitis pigmentosa.

• MERTK: Tyrosine-protein kinase Mer

  It promotes engulfment of apoptotic cells and dampens inflammatory responses after activation by GAS6 or protein S, with important roles in retinal pigment epithelium and immune cells. Biallelic loss-of-function variants cause retinitis pigmentosa, while tumor cells can exploit MERTK signaling for survival and immune evasion.

  11 disease-causing and 46 uncertain variants in MERTK are linked to Retinitis pigmentosa.

• NR2E3: Photoreceptor-specific nuclear receptor

  It directs rod-photoreceptor differentiation while repressing inappropriate cone gene programs during retinal development. Pathogenic variants cause enhanced S-cone syndrome, retinitis pigmentosa, and related inherited retinal dystrophies.

  11 disease-causing and 38 uncertain variants in NR2E3 are linked to Retinitis pigmentosa.

• RP2: Protein XRP2

  It regulates small-GTPase and ciliary trafficking processes required for photoreceptor maintenance. Loss-of-function variants cause X-linked retinitis pigmentosa, often with early-onset and severe rod-cone degeneration.

  10 disease-causing and 14 uncertain variants in RP2 are linked to Retinitis pigmentosa.

• BBS2: BBSome complex member BBS2

  It contributes to BBSome assembly and ciliary cargo trafficking, which are required for signaling in photoreceptors, kidney, hypothalamus, and other tissues. Biallelic loss-of-function variants cause Bardet-Biedl syndrome.

  8 disease-causing and 101 uncertain variants in BBS2 are linked to Retinitis pigmentosa.

• IFT172: Intraflagellar transport protein 172 homolog

  It supports intraflagellar transport required for assembly and maintenance of primary and sensory cilia. Biallelic pathogenic variants cause ciliopathies that can involve retinal degeneration, skeletal abnormalities, kidney disease, or Joubert-spectrum neurologic findings.

  7 disease-causing and 608 uncertain variants in IFT172 are linked to Retinitis pigmentosa.

• EYS: Protein eyes shut homolog

  6 disease-causing and 36 uncertain variants in EYS are linked to Retinitis pigmentosa.

• CNGA1: Cyclic nucleotide-gated channel alpha-1

  It forms part of the cyclic-GMP-gated conductance that depolarizes rod photoreceptors in darkness and closes after light activation lowers cGMP. Biallelic loss-of-function variants cause autosomal recessive retinitis pigmentosa with progressive rod-cone degeneration.

  6 disease-causing and 26 uncertain variants in CNGA1 are linked to Retinitis pigmentosa.

• RPGR: X-linked retinitis pigmentosa GTPase regulator

  It coordinates protein trafficking through the photoreceptor connecting cilium, which is essential for continual renewal of outer segments. Pathogenic variants are a major cause of X-linked retinitis pigmentosa and can also produce cone-rod dystrophy.

  4 disease-causing and 2 uncertain variants in RPGR are linked to Retinitis pigmentosa.

• RLBP1: Retinaldehyde-binding protein 1

  It binds 11-cis-retinoids in retinal pigment epithelium and Muller cells and supports regeneration and trafficking of visual-cycle chromophore. Biallelic pathogenic variants cause retinal dystrophies including Bothnia dystrophy, retinitis punctata albescens, and fundus albipunctatus-like disease.

  3 disease-causing and 9 uncertain variants in RLBP1 are linked to Retinitis pigmentosa.

• BEST1: Bestrophin-1

  It helps regulate ion transport and fluid homeostasis across the retinal pigment epithelium. Pathogenic variants cause bestrophinopathies including Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, and some retinitis pigmentosa phenotypes.

  2 disease-causing and 18 uncertain variants in BEST1 are linked to Retinitis pigmentosa.

• MYO7A: Unconventional myosin-VIIa

  Its actin-based motor supports stereocilia organization in inner-ear hair cells and transport processes in retinal cells. Biallelic pathogenic variants cause Usher syndrome type 1B, while other alleles can cause nonsyndromic hearing loss.

  2 disease-causing and 1 uncertain variants in MYO7A are linked to Retinitis pigmentosa.

• CRX: Cone-rod homeobox protein

  It activates photoreceptor-specific gene programs required for development and maintenance of rods and cones. Pathogenic variants can cause cone-rod dystrophy, Leber congenital amaurosis, or dominant retinitis pigmentosa depending on the molecular mechanism.

  1 disease-causing and 5 uncertain variants in CRX are linked to Retinitis pigmentosa.

• BBS1: BBSome complex member BBS1

  Within the BBSome, it helps control trafficking of membrane proteins into and out of primary cilia. Biallelic pathogenic variants cause Bardet-Biedl syndrome, with retinal degeneration, obesity, renal abnormalities, polydactyly, and variable neurodevelopmental features.

  1 disease-causing and 2 uncertain variants in BBS1 are linked to Retinitis pigmentosa.

• CLN3: Battenin

  It participates in lysosomal and endosomal homeostasis, membrane trafficking, and cellular lipid handling, although its complete molecular role remains unresolved. Biallelic loss-of-function variants cause juvenile neuronal ceroid lipofuscinosis, with progressive vision loss, epilepsy, cognitive decline, and motor impairment.

  1 disease-causing and 4 uncertain variants in CLN3 are linked to Retinitis pigmentosa.

• CHM: Rab proteins geranylgeranyltransferase component A 1

  It enables prenylation of Rab GTPases by delivering Rab proteins to geranylgeranyl transferase, supporting membrane trafficking in retinal and other cells. Loss-of-function variants cause X-linked choroideremia with progressive degeneration of photoreceptors, retinal pigment epithelium, and choroid.

  1 disease-causing and 0 uncertain variants in CHM are linked to Retinitis pigmentosa.

• CEP290: Centrosomal protein of 290 kDa

  It organizes the transition zone of primary and sensory cilia and is essential for ciliary protein trafficking, especially in photoreceptors. Biallelic pathogenic variants cause a broad ciliopathy spectrum including Leber congenital amaurosis, Joubert syndrome, and nephronophthisis-related disease.

  0 disease-causing and 1 uncertain variants in CEP290 are linked to Retinitis pigmentosa.

• ALMS1: Centrosome-associated protein ALMS1

  It contributes to primary-cilium function, intracellular trafficking, and metabolic homeostasis in multiple tissues. Biallelic pathogenic variants cause Alstrom syndrome, which typically combines retinal degeneration, hearing loss, obesity, insulin resistance, and cardiomyopathy.

  0 disease-causing and 0 uncertain variants in ALMS1 are linked to Retinitis pigmentosa.

• GNAT1: Guanine nucleotide-binding protein G(t) subunit alpha-1

  It transduces the light-activated rhodopsin signal in rod photoreceptors, activating phosphodiesterase and lowering cGMP to initiate visual responses. Pathogenic variants can cause congenital stationary night blindness or autosomal dominant rod-cone degeneration.

  1 disease-causing and 1 uncertain variants in GNAT1 are linked to Retinitis pigmentosa.

Weakly linked (only a few uncertain records): BBS4, COL2A1, OPA1, SLC34A3 and WDR19.

Where Retinitis pigmentosa variants cluster

• PRPH2 Lumenal (positions 124–264): 14 of 14 disease-causing changes, 2.5× more than its size predicts.
• RHO Extracellular (positions 174–202): 17 of 65 disease-causing changes, 3.1× more than its size predicts.
• MERTK Protein kinase (positions 587–858): 9 of 11 disease-causing changes, 3.0× more than its size predicts.
• PDE6B PDEase (positions 481–814): 12 of 15 disease-causing changes, 2.0× more than its size predicts.
• CRB1 EGF-like 19 (positions 1297–1333): 9 of 128 disease-causing changes, 2.7× more than its size predicts.

Known disease-causing variants in Retinitis pigmentosa

Showing 60 of 399.

Uncertain variants in Retinitis pigmentosa that look disease-causing

Which prediction tools work for Retinitis pigmentosa

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• EVE: 96 out of 100
• AlphaMissense: 94 out of 100
• MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 85 out of 100
• AlphaGenome (regulatory): 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 68 out of 100
• AlphaGenome (splicing): 42 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Leber congenital amaurosis is also caused by CRB1 variants; they fall partly in the same places as the Retinitis pigmentosa variants (141 disease-causing).
• Pigmentary retinal dystrophy is also caused by RHO variants; they fall in the same places as the Retinitis pigmentosa variants (5 disease-causing).
• Severe early-childhood-onset retinal dystrophy is also caused by ABCA4 variants; they fall mostly in different places as the Retinitis pigmentosa variants (148 disease-causing).
• ABCA4-related retinopathy is also caused by ABCA4 variants; they fall mostly in different places as the Retinitis pigmentosa variants (60 disease-causing).
• Stargardt disease is also caused by ABCA4 variants; they fall mostly in different places as the Retinitis pigmentosa variants (41 disease-causing).
• Age related macular degeneration 9 is also caused by ABCA4 variants; they fall mostly in different places as the Retinitis pigmentosa variants (41 disease-causing).
• Cone-rod dystrophy is also caused by ABCA4 variants; they fall mostly in different places as the Retinitis pigmentosa variants (29 disease-causing).
• Usher syndrome is also caused by USH2A variants; they fall mostly in different places as the Retinitis pigmentosa variants (40 disease-causing).
• RPE65-related recessive retinopathy is also caused by RPE65 variants; they fall mostly in different places as the Retinitis pigmentosa variants (83 disease-causing).
• Leber congenital amaurosis is also caused by RPE65 variants; they fall partly in the same places as the Retinitis pigmentosa variants (29 disease-causing).

Diseases related to Retinitis pigmentosa

• Autosomal recessive retinitis pigmentosa, also linked to ABCA4, CRB1, EYS, MERTK and 4 more
• Leber congenital amaurosis, also linked to ABCA4, ALMS1, CEP290, CRB1 and 2 more
• Cone-rod dystrophy, also linked to ABCA4, CRB1, CRX, PRPH2 and 2 more
• Bardet-Biedl syndrome, also linked to ALMS1, BBS1, BBS2, CEP290 and 1 more
• Retinal disorder, also linked to ABCA4, BEST1, PRPH2, RHO and 1 more
• Congenital stationary night blindness autosomal dominant 3, also linked to ABCA4, GNAT1, PDE6B and RHO
• Pigmentary retinal dystrophy, also linked to PRPH2, RHO and RLBP1
• Severe early-childhood-onset retinal dystrophy, also linked to ABCA4 and CRB1
• Usher syndrome, also linked to MYO7A and USH2A
• Rare genetic deafness, also linked to MYO7A and USH2A
• Stargardt disease, also linked to ABCA4 and PRPH2
• Vitelliform macular dystrophy 2, also linked to BEST1 and PRPH2

Frequently asked questions

Which genes are linked to Retinitis pigmentosa?

In CATVariant, Retinitis pigmentosa is linked to 25 analyzed proteins: CRB1 (Protein crumbs homolog 1), RHO (Rhodopsin), ABCA4 (Retinal-specific phospholipid-transporting ATPase ABCA4), USH2A (Usherin), RPE65 (Retinoid isomerohydrolase), PDE6B (Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta) and 19 more.

How many genetic variants are linked to Retinitis pigmentosa?

2,744 variants: 399 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,850 are of uncertain significance or have conflicting reports.

Which uncertain variants in Retinitis pigmentosa look disease-causing?

14 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CRB1 G1288D, CRB1 G899V, CRB1 C438Y, CRB1 G615D and CRB1 C939Y. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Retinitis pigmentosa?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 78 disease-causing and 42 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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