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Abstract Synonymous single nucleotide variants (sSNVs) do not alter the primary structure of a protein, thus it was previously accepted that they were neutral. Recently, several studies demonstrated their significance to a range of diseases. Still, variant prioritization strategies lack focus on sSNVs. Here, we identified 22,841 deleterious synonymous variants in 125,748 human exomes using two in silico predictors (SilVA and CADD). While 98.2% of synonymous variants are classified as neutral, 1.8% are predicted to be deleterious, yielding an average of 9.82 neutral and 0.18 deleterious sSNVs per exome. Further investigation of prediction features via Heterogeneous Ensemble Feature Selection revealed that impact on amino acid sequence and conservation carry the most weight for a deleterious prediction. Thirty nine detrimental sSNVs are not rare and are located on disease associated genes. Ten distinct putatively non-deleterious sSNVs are likely to be under positive selection in the North-Western European and East Asian populations. Taken together our analysis gives voice to the so-called silent mutations as we propose a robust framework for evaluating the deleteriousness of sSNVs in variant prioritization studies.