PAH and phenylketonuria: The nucleotide aberrations c.721C>T and c.728 G>A in PAH exon 7 code for the p.Arg241Cys (p.R241C) and p.Arg243Gln (R243Q) mutations and are some of the most abundant mutations among PKU patients, with an average allele frequency of approximately 6% (9–14% in Mediterranean countries and the Middle East), with ~ 2% of patients homozygous for this mutation (up to 12% in Mediterranean countries and the Middle East)9,21.The PAH protein exists in two distinct conformations22,23, an auto-inhibited PAH illustrated in Fig. 1a and an activated PAH conformation (not shown).