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A synonymous substitution (also called a silent substitution) is the evolutionary substitution of one base for another in a gene coding for a protein, such that the protein sequence produced is not modified.

Proteins translation involves a set of twenty amino acids. Each of these amino acids is coded for by a sequence of three DNA base pairs called a codon. Because there are 64 possible codons, but only 20 amino acids (as well as a stop signal, indicating that translation should stop), some amino acids are coded for by 2, 3, 4, or 6 different codons. For example, the codons TTT and TTC both code for the amino acid phenylalanine. This is often referred to as redundancy of the genetic code. There are two mechanisms for redudancy: several different transfer RNAs can deliver the same amino acid, or one tRNA can have a non-standard "wobbly" base in position three of the anti-codon, which recognises more than one base in the codon.

In the above phenylalanine example, suppose that the base in position 3 of a TTT codon got substituted to a C, leaving the codon TTC. The amino acid at that position in the protein will remain a phenylalanine. Hence, the substitution is a synonymous one.

Although mutation and substitution are often used interchangably, there is a subtle but important difference. A nucleotide mutation is a base change (whether synonymous or non-synonymous) such that the mutant and wild-type forms coexist in a population. A nucleotide substitution is a base change between two related species. Thus, a mutation only becomes a substitution after it has increased to 100% frequency, or fixed, in the species.

When a synonymous or silent mutation occurs, the change is generally neutral, meaning that it does not affect the fitness of the individual carrying the new gene to survive and reproduce. Redundancy of the genetic code provides some protection against the effect of mutations.

Substitutions that are not synonymous are often detrimental to the host cell. For instance, a mammalian cell might have a gene coding for a protein that regulates cell division. A mutation that results in a change to the methionine codon that marks the beginning of the gene's open reading frame may cause the gene to become inactivated. The protein that regulates cell division would not be produced, and the cell would grow unchecked, resulting in a tumor cell.