rs5030858

Phenylketonuria

The rs5030858 A allele (p.Arg408Trp) is a well-established pathogenic variant in the PAH gene, uniformly classified as Pathogenic across all ClinVar submissions for phenylketonuria. In the largest epidemiological study of PKU to date (n=16,092 patients across 51 countries), c.1222C>T (p.Arg408Trp) was the most prevalent PAH variant, accounting for 22.2% of all disease alleles; homozygotes (p.[Arg408Trp];[Arg408Trp]) comprised 11.4% of all genotypes and present with classic severe PKU. The mutation is predominantly found in Eastern European and Balto-Slavic populations but occurs globally. Homozygous or compound heterozygous carriers present with markedly elevated blood phenylalanine, intellectual disability if untreated, and are generally BH4 non-responsive.