The genetic code is read in continuous triplets. A frameshift mutation inserts or deletes nucleotides in a number not divisible by three, shifting the reading frame of every codon downstream. The resulting protein is usually truncated or filled with incorrect amino acids.

Even a single-base insertion or deletion can destroy protein function. Nonsense-mediated decay often degrades the abnormal messenger RNA, leading to loss of the gene product. Frameshifts are frequently more damaging than simple amino-acid substitutions.

Many disease-causing alleles, including certain mutations in the CFTR and dystrophin genes, are frameshifts. Sequencing detects them readily. Because the effect is so disruptive, frameshift mutations are rarely tolerated in essential genes and are strongly selected against.

• Insertion or deletion not divisible by three
• Shifts the codon reading frame
• Usually produces nonfunctional protein
• Commonly causes severe loss-of-function