ABCA4-related retinopathy: genes and variants

Genes linked to ABCA4-related retinopathy

• 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.

  60 disease-causing and 28 uncertain variants in ABCA4 are linked to ABCA4-related retinopathy.

Where ABCA4-related retinopathy variants cluster

• ABCA4 ABC transporter 2 (positions 1938–2170): 18 of 60 disease-causing changes, 2.9× more than its size predicts.
• ABCA4 Cytoplasmic (positions 1–21): 3 of 60 disease-causing changes, 5.4× more than its size predicts.
• ABCA4 Extracellular (positions 1853–1873): 3 of 60 disease-causing changes, 5.4× more than its size predicts.
• ABCA4 ABC transporter 1 (positions 929–1160): 10 of 60 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in ABCA4-related retinopathy

Which prediction tools work for ABCA4-related retinopathy

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)
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 89 out of 100
• phyloP: 86 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 ABCA4-related retinopathy variants (148 disease-causing).
• Retinitis pigmentosa is also caused by ABCA4 variants; they fall mostly in different places as the ABCA4-related retinopathy variants (58 disease-causing).
• Stargardt disease is also caused by ABCA4 variants; they fall mostly in different places as the ABCA4-related retinopathy variants (41 disease-causing).
• Age related macular degeneration 9 is also caused by ABCA4 variants; they fall mostly in different places as the ABCA4-related retinopathy variants (41 disease-causing).
• Cone-rod dystrophy is also caused by ABCA4 variants; they fall mostly in different places as the ABCA4-related retinopathy variants (29 disease-causing).

Diseases related to ABCA4-related retinopathy

• Retinitis pigmentosa, also linked to ABCA4
• Leber congenital amaurosis, also linked to ABCA4
• Severe early-childhood-onset retinal dystrophy, also linked to ABCA4
• Stargardt disease, also linked to ABCA4
• Cone-rod dystrophy, also linked to ABCA4
• Age related macular degeneration 9, also linked to ABCA4
• Retinal disorder, also linked to ABCA4
• Optic atrophy, also linked to ABCA4
• Congenital stationary night blindness autosomal dominant 3, also linked to ABCA4
• Autosomal recessive retinitis pigmentosa, also linked to ABCA4
• Isolated macular dystrophy, also linked to ABCA4

Frequently asked questions

Which genes are linked to ABCA4-related retinopathy?

In CATVariant, ABCA4-related retinopathy is linked to 1 analyzed protein: ABCA4 (Retinal-specific phospholipid-transporting ATPase ABCA4).

How many genetic variants are linked to ABCA4-related retinopathy?

100 variants: 60 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 28 are of uncertain significance or have conflicting reports.

Which uncertain variants in ABCA4-related retinopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for ABCA4-related retinopathy?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 51 disease-causing and 27 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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