This study aimed to identify serum proteomic features distinguishing genetically distinct but clinically overlapping subtypes of macula-predominant inherited retinal degeneration (MP-IRD). We also assessed the potential utility of these features as diagnostic biomarkers. Serum samples from age-matched patients carrying molecularly confirmed mutations in ABCA4, BEST1, PROM1, or GUCY2D were analyzed. Following the depletion of abundant serum proteins, liquid chromatography–tandem mass spectrometry (LC-MS/MS) was employed to identify differentially expressed proteins (DEPs). Proteomic data were evaluated through clustering, principal component analysis (PCA), and gene ontology (GO) enrichment to uncover biological patterns associated with genotype-specific molecular pathways. Candidate biomarkers were validated in an expanded patient cohort using enzyme-linked immunosorbent assays (ELISAs). LC-MS/MS detected 329 prominent serum proteins and revealed distinct DEP expression profiles across the four genotypes. Pairwise comparison between ABCA4 and BEST1 showed the most significant separation in both PCA and clustering analyses, suggesting strong proteomic divergence. GO enrichment revealed shared stress-adaptive responses across all groups and genotype-specific functional enrichment in lipid metabolism (ABCA4), peptidyl-prolyl isomerase activity (GUCY2D), and synaptic vesicle exocytosis (BEST1). These findings indicate that systemic proteomic differences reflect disease mechanisms underlying retinal degeneration. Validation using ELISA in an expanded cohort confirmed significantly elevated serum synaptic vesicle 2-related protein (SVOP) levels in patients with BEST1-associated MP-IRD (p = 0.0004). SVOP, a presynaptic membrane protein involved in vesicular trafficking, emerged as a potential BEST1-specific biomarker that may reflect synaptic remodeling and blood-retina barrier disruption. In conclusion, this study delineates the serum proteomic landscape of MP-IRDs and demonstrates that proteomic profiling can serve as a promising, non-invasive diagnostic approach. Identification of SVOP as a BEST1-related biomarker enhances understanding of genotype-specific disease mechanisms and underscores the clinical potential of serum proteomics for differential diagnosis and molecular insight into inherited retinal degenerations. These findings highlight the potential of serum proteomics for differential diagnosis and mechanistic insights in MP-IRDs.