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Homozygous mutations resulting in below 10% enzyme activity can occur, although they are particularly rare.[60] Greater than 65 naturally occurring mutations that result in modifications of the CPOX gene in humans have been reported, with the majority producing missense, frameshift, nonsense, insertion/deletion mutations and substitutions of amino acid residues.[35,61] Unlike mutations in HMBS (AIP) of which 60% mutation are clustered between three exons, mutations in CPOX are spread throughout the gene