The differential use of synonymous codons of an amino acid is an imperative evolutionary phenomenon, termed codon usage bias, that functions across various levels of organisms. It is accustomed to providing an understanding of a gene's differential architecture driven by functional regulation of gene expression. Numerous synonymous mutations are linked to various diseases, demonstrating that silent mutations can be deleterious. We employed bioinformatics methods to examine codon usage trends in 263 coding sequences of 44 blood group systems. The blood group systems were categorized into two groups based on association with a sort of neurodegenerative disorder. We performed a CUB study to investigate how multiple components, such as selection, mutation and biased nucleotide composition are accountable for the evolution of the transcripts of the blood group antigens. The compositional analysis implicated blood group genes were GC-rich. RSCU analysis showed G/C-ending codon choice among synonymous codons. Also, a distinct codon choice was found in both blood groups for serine and proline. Moreover, the leucine-coding CTG codon was found the most overrepresented in all the genes, indicating selectional pressure substantially impacts overall codon usage. This was also supported by biplot analysis. Additionally, CpC and GpG overrepresentation is in concordance with the results concerning neurodegenerative disorders where CpC has been attributed to non-CpG methylation and linked to several neurodegenerative ailments. Both the Z-test analysis and rare codon choice showed a substantial difference in codon usage by the genes of both groups.