GUCY2D encodes photoreceptor guanylate cyclase (GC-E), which catalyzes cGMP synthesis in rod and cone photoreceptors and plays an essential role in phototransduction by mediating cGMP replenishment 1. The enzyme is regulated by intracellular Ca2+-sensor proteins called guanylate cyclase-activating proteins (GCAPs), and alterations in Ca2+-sensitivity represent a key mechanism of disease 1. GUCY2D mutations account for approximately 1.7% of inherited retinal disease cases in large cohorts 2. Over 140 disease-causing mutations have been identified, with 88% causing autosomal recessive Leber congenital amaurosis (LCA)—one of the most severe early-onset retinal dystrophies—while heterozygous missense mutations cause autosomal dominant cone-rod dystrophy (adCRD) 1. GUCY2D is among the five most frequently mutated genes in LCA patients, with prevalence reaching 7.7% in some populations 3. A clear genotype-phenotype correlation exists: LCA-causing mutations show reduced or absent cGMP synthetic ability, while CRD-causing mutations retain function but alter GCAP binding 1. Mutation type (missense versus null) and localization within functional domains determine inheritance pattern and enzymatic impact 1. Gene augmentation therapy in animal models has yielded promising results, positioning GUCY2D as a candidate for therapeutic intervention.