RNA editing is one of the most common RNAlevel modifications that potentially generate aminoacid changes similar to those resulting from ge-nomic nonsynonymous mutations. However, unlikeDNA level allele-specific modifications such as DNAmethylation, it is currently unknown whether RNAediting displays allele-specificity across tissues andspecies. Here, we analyzed allele-specific RNA edit-ing in human tissues and from brain tissues of het-erozygousmicegeneratedbycrossesbetweendiver-gent mouse strains and found a high proportion ofoverlap of allele-specific RNA editing sites betweendifferent samples. We identified three allele-specificRNA editing sites cause amino acid changes in cod-ing regions of human and mouse genes, whereastheir associated SNPs yielded synonymous differ-ences. In vitro cellular experiments confirmed thatsequences differing at a synonymous SNP can havedifferences in a linked allele-specific RNA editingsite with nonsynonymous implications. Further, wedemonstrate that allele-specific RNA editing is influ-enced by differences in local RNA secondary struc-ture generated by SNPs. Our study provides new in-sights towards a better comprehension of the molec-ular mechanism that link SNPs with human diseasesand traits.