A
synonymous substitution (often called a
silent substitution though they are not always silent) is the evolutionary substitution of one
base for another in an
exon of a
gene coding for a
protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair
codon; since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing polypeptide chain when the gene is translated. Synonymous substitutions and mutations affecting
noncoding DNA are often considered
silent mutations; however, it is not always the case that the mutation is silent. Synonymous mutations can affect
transcription,
splicing,
mRNA transport, and
translation, any of which could alter
phenotype, rendering the synonymous mutation non-silent. The substrate specificity of the
tRNA to the rare codon can affect the timing of translation, and in turn the co-translational folding of the protein. This is reflected in the
codon usage bias that is observed in many species. A
nonsynonymous substitution results in a change in amino acid that may be arbitrarily further classified as conservative (change to an amino acid with similar physiochemical properties), semi-conservative (e.g. negative to positively charged amino acid), or radical (vastly different amino acid).