The effects of synonymous single nucleotide variants (sSNVs) are often neglected since they do not alter protein primary structure. Nevertheless, there is growing evidence that synonymous variations may impact mRNA expression, protein conformation and activity which may lead to protein deficiency and disease manifestations. As there are more than 21 million possible sSNVs affecting human genome, it is not feasible to experimentally validate the effect of each sSNV. Here, we report a comprehensive series of in-silico analyses assessing sSNV impact on a specific gene. A Disintegrin-like and Metalloprotease with Thrombospondin type-1 repeats, member-13 (ADAMTS13) was chosen as a model for its large size, many previously reported sSNVs and associated coagulopathy thrombotic thrombocytopenic purpura (TTP). Using various prediction tools of biomolecular characteristics, we evaluated all ADAMTS13 sSNVs registered in the NCBI dbSNP, including 357 neutral sSNVs and 19 sSNVs identified in TTP patients. We showed that some sSNVs change mRNA folding energy/stability, disrupt mRNA splicing, disturb micro RNAs (miRNAs) binding sites, and alter synonymous codon or codon pair usage. Our findings highlight the importance of considering sSNVs when assessing the complex effects of ADAMTS13 alleles and our approach provides a generalizable framework to characterize sSNV impact in other genes and diseases.