Stargardt disease: genes and variants

Genes linked to Stargardt disease

• 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.

  41 disease-causing and 14 uncertain variants in ABCA4 are linked to Stargardt disease.

• 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.

  4 disease-causing and 8 uncertain variants in PRPH2 are linked to Stargardt disease.

Weakly linked (only a few uncertain records): BEST1 and RP2.

Where Stargardt disease variants cluster

• ABCA4 Cytoplasmic (positions 1–21): 4 of 41 disease-causing changes, 10.6× more than its size predicts.
• ABCA4 Extracellular (positions 781–835): 3 of 41 disease-causing changes, 3.0× more than its size predicts.

Known disease-causing variants in Stargardt disease

Which prediction tools work for Stargardt disease

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

• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 87 out of 100
• phyloP: 86 out of 100
• MetaLR: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Severe early-childhood-onset retinal dystrophy is also caused by ABCA4 variants; they fall mostly in different places as the Stargardt disease variants (148 disease-causing).
• ABCA4-related retinopathy is also caused by ABCA4 variants; they fall mostly in different places as the Stargardt disease variants (60 disease-causing).
• Retinitis pigmentosa is also caused by ABCA4 variants; they fall mostly in different places as the Stargardt disease variants (58 disease-causing).
• Age related macular degeneration 9 is also caused by ABCA4 variants; they fall mostly in different places as the Stargardt disease variants (41 disease-causing).
• Cone-rod dystrophy is also caused by ABCA4 variants; they fall mostly in different places as the Stargardt disease variants (29 disease-causing).
• Retinitis pigmentosa is also caused by PRPH2 variants; they fall mostly in different places as the Stargardt disease 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 Stargardt disease variants (11 disease-causing).
• Pigmentary retinal dystrophy is also caused by PRPH2 variants; they fall mostly in different places as the Stargardt disease variants (3 disease-causing).
• Patterned macular dystrophy 1 is also caused by PRPH2 variants; they fall mostly in different places as the Stargardt disease variants (3 disease-causing).
• Vitelliform macular dystrophy 2 is also caused by PRPH2 variants; they fall mostly in different places as the Stargardt disease variants (3 disease-causing).

Diseases related to Stargardt disease

• Retinitis pigmentosa, also linked to ABCA4 and PRPH2
• Cone-rod dystrophy, also linked to ABCA4 and PRPH2
• Retinal disorder, also linked to ABCA4 and PRPH2
• Leber congenital amaurosis, also linked to ABCA4
• Severe early-childhood-onset retinal dystrophy, also linked to ABCA4
• ABCA4-related retinopathy, also linked to ABCA4
• Age related macular degeneration 9, also linked to ABCA4
• Vitelliform macular dystrophy 2, also linked to PRPH2
• Patterned dystrophy of the retinal pigment epithelium, also linked to PRPH2
• Optic atrophy, also linked to ABCA4
• Congenital stationary night blindness autosomal dominant 3, also linked to ABCA4
• Pigmentary retinal dystrophy, also linked to PRPH2

Frequently asked questions

Which genes are linked to Stargardt disease?

In CATVariant, Stargardt disease is linked to 2 analyzed proteins: ABCA4 (Retinal-specific phospholipid-transporting ATPase ABCA4) and PRPH2 (Peripherin-2).

How many genetic variants are linked to Stargardt disease?

96 variants: 45 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 24 are of uncertain significance or have conflicting reports.

Which uncertain variants in Stargardt disease 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 Stargardt disease?

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 36 disease-causing and 59 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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