Human retinal gene 4 (HRG4) (UNC119) is a photoreceptor synaptic protein of unknown function, shown when mutated to cause retinal degeneration in a patient and in a confirmatory transgenic model. ADP‐ribosylation factor‐like protein 2 (ARL2) was identified as an interactor of HRG4 by the yeast two‐hybrid strategy. The presence of ARL2 in the retina and co‐localization with HRG4 was confirmed by Western blot and double immunofluorescence analysis, respectively. The interaction of ARL2 with HRG4 was further confirmed by co‐immunoprecipitation and direct binding analysis. Phosphodiesterase δ (PDEδ) is an ARL2‐binding protein homologous to HRG4. Amino acid residues of PDEδ involved in binding ARL2 and forming a hydrophobic pocket were shown to be highly conserved in HRG4, suggesting similarity in binding mechanism and function.