Cone-rod dystrophy: genes and variants
Cone-rod dystrophy is linked to 7 analyzed proteins (ABCA4, CRX, PRPH2, CRB1, CREBBP, USH2A and RPGR). 44 DNA variants are known to cause it; 173 more are uncertain, and 3 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Cone rod dystrophy; Cone-rod dystrophy 15; cone-rod dystrophy 2; cone-rod dystrophy 3; Cone-rod dystrophy 6
Genes linked to Cone-rod dystrophy
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.
29 disease-causing and 29 uncertain variants in ABCA4 are linked to Cone-rod dystrophy.
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.
11 disease-causing and 125 uncertain variants in CRX are linked to Cone-rod dystrophy.
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.
2 disease-causing and 10 uncertain variants in PRPH2 are linked to Cone-rod dystrophy.
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.
1 disease-causing and 2 uncertain variants in CRB1 are linked to Cone-rod dystrophy.
CREBBP: CREB-binding protein
It acetylates histones and integrates signals from many transcription factors to regulate developmental and activity-dependent gene expression. Germline loss-of-function variants cause Rubinstein-Taybi syndrome, while somatic alterations occur in several cancers.
1 disease-causing and 0 uncertain variants in CREBBP are linked to Cone-rod dystrophy.
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.
0 disease-causing and 1 uncertain variants in USH2A are linked to Cone-rod dystrophy.
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.
0 disease-causing and 0 uncertain variants in RPGR are linked to Cone-rod dystrophy.
Weakly linked (only a few uncertain records): RPE65, BEST1, CNGA1, MECP2, MERTK, OPA1 and PDE6B.
Where Cone-rod dystrophy variants cluster
- CRX Homeobox (positions 39–98): 11 of 11 disease-causing changes, 5.0× more than its size predicts.
Known disease-causing variants in Cone-rod dystrophy
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| ABCA4 R2106H | 2106 | ABC transporter 2 | Disease-causing (★★) |
| ABCA4 R2106C | 2106 | ABC transporter 2 | Disease-causing (★★) |
| CRX R43H | 43 | Homeobox | Disease-causing (★★) |
| CRX R43C | 43 | Homeobox | Disease-causing (★★) |
| ABCA4 E328V | 328 | Extracellular | Disease-causing (★★) |
| ABCA4 P640S | 640 | Extracellular | Disease-causing (★★) |
| ABCA4 L2060R | 2060 | ABC transporter 2 | Disease-causing (★★) |
| CRB1 C1294Y | 1294 | EGF-like 18 | Disease-causing (★★) |
| CREBBP C1729R | 1729 | ZZ-type | Disease-causing (★★) |
| ABCA4 C54G | 54 | Extracellular | Disease-causing (★★) |
| ABCA4 A60V | 60 | Extracellular | Disease-causing (★★) |
| ABCA4 G607R | 607 | Extracellular | Disease-causing (★★) |
| ABCA4 D1102Y | 1102 | ABC transporter 1 | Disease-causing (★★) |
| ABCA4 C1488F | 1488 | Extracellular | Disease-causing (★★) |
| ABCA4 I1846T | 1846 | Transmembrane | Disease-causing (★★) |
| CRX R40Q | 40 | Homeobox | Disease-causing (★★) |
| CRX R41W | 41 | Homeobox | Disease-causing (★★) |
| CRX R69C | 69 | Homeobox | Disease-causing (★★) |
| CRX R69H | 69 | Homeobox | Disease-causing (★★) |
| ABCA4 E328K | 328 | Extracellular | Disease-causing (★★) |
| ABCA4 L844R | 844 | Transmembrane | Disease-causing (★★) |
| ABCA4 F2188S | 2188 | Cytoplasmic | Disease-causing (★★) |
| CRX E80A | 80 | Homeobox | Disease-causing (★★) |
| ABCA4 R24C | 24 | Transmembrane | Disease-causing (★★) |
| ABCA4 L611P | 611 | Extracellular | Disease-causing (★★) |
| ABCA4 F655C | 655 | Transmembrane | Disease-causing (★★) |
| ABCA4 F938S | 938 | ABC transporter 1 | Disease-causing (★★) |
| ABCA4 R1443C | 1443 | Extracellular | Disease-causing (★★) |
| ABCA4 H1625Y | 1625 | Extracellular | Disease-causing (★★) |
| ABCA4 R2040Q | 2040 | ABC transporter 2 | Disease-causing (★★) |
| PRPH2 R195Q | 195 | Lumenal | Disease-causing (★★) |
| PRPH2 I196N | 196 | Lumenal | Disease-causing (★★) |
| ABCA4 V675I | 675 | Cytoplasmic | Disease-causing (★★) |
| ABCA4 S1696N | 1696 | Extracellular | Disease-causing (★★) |
| CRX K88R | 88 | Homeobox | Disease-causing (★★) |
| ABCA4 R187H | 187 | Extracellular | Disease-causing (★★) |
| ABCA4 M448V | 448 | Extracellular | Disease-causing (★★) |
| ABCA4 G991V | 991 | ABC transporter 1 | Disease-causing (★★) |
| CRX R43S | 43 | Homeobox | Disease-causing (★) |
| CRX E80K | 80 | Homeobox | Disease-causing (★) |
| ABCA4 M1115R | 1115 | ABC transporter 1 | Disease-causing (★) |
| ABCA4 L1631P | 1631 | Extracellular | Disease-causing (★) |
| CRX R90W | 90 | Homeobox | Disease-causing |
| ABCA4 A1762D | 1762 | Transmembrane | Disease-causing |
Uncertain variants in Cone-rod dystrophy that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| CRX R90Q | 90 | Homeobox | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R90W at the same position is pathogenic; REVEL 0.901 |
| CRX R43L | 43 | Homeobox | Uncertain (★) | +6: 5 other pathogenic changes within 3 positions; R43H at the same position is pathogenic; REVEL 0.970 |
| CRX R69G | 69 | Homeobox | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; R69C at the same position is pathogenic; REVEL 0.834 |
Which prediction tools work for Cone-rod dystrophy
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MutPred2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 91 out of 100
- CADD: 91 out of 100
- SIFT: 89 out of 100
- MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 71 out of 100
Same protein, different disease
- Severe early-childhood-onset retinal dystrophy is also caused by ABCA4 variants; they fall mostly in different places as the Cone-rod dystrophy variants (148 disease-causing).
- ABCA4-related retinopathy is also caused by ABCA4 variants; they fall mostly in different places as the Cone-rod dystrophy variants (60 disease-causing).
- Retinitis pigmentosa is also caused by ABCA4 variants; they fall mostly in different places as the Cone-rod dystrophy variants (58 disease-causing).
- Stargardt disease is also caused by ABCA4 variants; they fall mostly in different places as the Cone-rod dystrophy variants (41 disease-causing).
- Age related macular degeneration 9 is also caused by ABCA4 variants; they fall mostly in different places as the Cone-rod dystrophy variants (41 disease-causing).
- Retinitis pigmentosa is also caused by PRPH2 variants; they fall mostly in different places as the Cone-rod dystrophy variants (14 disease-causing).
- Patterned dystrophy of the retinal pigment epithelium is also caused by PRPH2 variants; they fall mostly in different places as the Cone-rod dystrophy variants (11 disease-causing).
- Stargardt disease is also caused by PRPH2 variants; they fall mostly in different places as the Cone-rod dystrophy variants (4 disease-causing).
- Pigmentary retinal dystrophy is also caused by PRPH2 variants; they fall mostly in different places as the Cone-rod dystrophy variants (3 disease-causing).
- Vitelliform macular dystrophy 2 is also caused by PRPH2 variants; they fall mostly in different places as the Cone-rod dystrophy variants (3 disease-causing).
- Leber congenital amaurosis is also caused by CRB1 variants; they fall mostly in different places as the Cone-rod dystrophy variants (141 disease-causing).
- Retinitis pigmentosa is also caused by CRB1 variants; they fall mostly in different places as the Cone-rod dystrophy variants (128 disease-causing).
- Pigmented paravenous retinochoroidal atrophy is also caused by CRB1 variants; they fall mostly in different places as the Cone-rod dystrophy variants (11 disease-causing).
- Rubinstein-Taybi syndrome due to CREBBP mutations is also caused by CREBBP variants; they fall mostly in different places as the Cone-rod dystrophy variants (52 disease-causing).
- Menke-Hennekam syndrome is also caused by CREBBP variants; they fall mostly in different places as the Cone-rod dystrophy variants (15 disease-causing).
- Rubinstein-Taybi syndrome is also caused by CREBBP variants; they fall mostly in different places as the Cone-rod dystrophy variants (15 disease-causing).
Diseases related to Cone-rod dystrophy
- Retinitis pigmentosa, also linked to ABCA4, CRB1, CRX, PRPH2 and 2 more
- Leber congenital amaurosis, also linked to ABCA4, CRB1 and CRX
- Retinal disorder, also linked to ABCA4, PRPH2 and USH2A
- Autosomal recessive retinitis pigmentosa, also linked to ABCA4, CRB1 and USH2A
- Severe early-childhood-onset retinal dystrophy, also linked to ABCA4 and CRB1
- Stargardt disease, also linked to ABCA4 and PRPH2
- Usher syndrome, also linked to USH2A
- Rare genetic deafness, also linked to USH2A
- ABCA4-related retinopathy, also linked to ABCA4
- Rubinstein-Taybi syndrome due to CREBBP mutations, also linked to CREBBP
- Age related macular degeneration 9, also linked to ABCA4
- Vitelliform macular dystrophy 2, also linked to PRPH2
Frequently asked questions
Which genes are linked to Cone-rod dystrophy?
In CATVariant, Cone-rod dystrophy is linked to 7 analyzed proteins: ABCA4 (Retinal-specific phospholipid-transporting ATPase ABCA4), CRX (Cone-rod homeobox protein), PRPH2 (Peripherin-2), CRB1 (Protein crumbs homolog 1), CREBBP (CREB-binding protein), USH2A (Usherin) and 1 more.
How many genetic variants are linked to Cone-rod dystrophy?
271 variants: 44 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 173 are of uncertain significance or have conflicting reports.
Which uncertain variants in Cone-rod dystrophy look disease-causing?
3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CRX R90Q, CRX R43L and CRX R69G. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Cone-rod dystrophy?
Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 16 disease-causing and 218 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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