Genetic variants of ABCA4 are associated with a spectrum of inherited retinal degenerations, causing progressive vision loss due to rod and cone photoreceptor death and retinal pigment epithelium atrophy, ultimately leading to blindness. Understanding the functional implications and assessing the pathogenicity of the extensive number of ABCA4 variants, which exceed 3000, remains a formidable challenge. A substantial proportion of these variants remain categorized as variants of uncertain significance (VUS) or exhibit conflicting clinical interpretations (CI). Determining variant pathogenicity is imperative for clinicians to assess long-term outcomes and facilitate precise patient enrollment in ongoing clinical trials. This review aims to provide an overview of the current methodologies used to assess the functional characteristics of ABCA4 variants.