PAH rs5030870: PKU Carrier Status and Genotype Guide

What each genotype means

What the SNP Is and Where It Sits

This variant is a single base substitution situated in exon 12 of the PAH gene on chromosome 12 at 12q23.2. At the coding transcript level, it is characterized as NM_000277.3:c.1222C>T. Because the PAH gene is transcribed from the genomic minus strand, reference databases often show the forward genomic base change as G>A, while clinical genetics nomenclature refers directly to the mRNA coding change c.1222C>T. This alteration changes the codon from CGG (encoding arginine) to TGG (encoding tryptophan) at amino acid position 408 of the polypeptide chain. In clinical studies and carrier panels, it is frequently cited under the protein notation p.Arg408Trp or R408W. Catalog records may list this variant as rs5030870, while authoritative repositories such as dbSNP maintain it under the primary accession rs5030858.

What the PAH Gene Does

The PAH gene encodes the hepatic enzyme phenylalanine hydroxylase. Operating as a tetrameric, iron- and tetrahydrobiopterin-dependent enzyme, it catalyzes the rate-limiting step in dietary phenylalanine catabolism by converting L-phenylalanine into L-tyrosine. Codon 408 is located within the catalytic domain near the enzyme's oligomerization and active sites. Replacing the polar, positively charged arginine with a bulky, hydrophobic tryptophan residue disrupts the protein's native three-dimensional folding and stability. In vitro and in vivo enzymatic assessments demonstrate that the mutant p.Arg408Trp protein retains less than 2% to 5% of wild-type catalytic function. Without sufficient enzymatic activity, the body cannot process phenylalanine properly, leading to toxic accumulation in blood and central nervous system tissues.

Research Associations and Clinical Evidence

The link between the PAH p.Arg408Trp variant and phenylketonuria is supported by extensive functional validation and clinical research. The ClinGen Phenylketonuria Variant Curation Expert Panel classifies this variant in ClinVar as Pathogenic for classic phenylketonuria. Because PKU follows an autosomal recessive pattern of inheritance, having a single copy of the variant does not cause clinical disease. Heterozygous carriers maintain adequate enzyme function, standard cognitive outcomes, and normal blood phenylalanine levels under ordinary dietary conditions. However, individuals homozygous for the variant, or compound heterozygous with another severe PAH mutation, cannot metabolize phenylalanine effectively. If left unmanaged from infancy, severe hyperphenylalaninemia causes irreversible intellectual disability, seizures, microcephaly, and developmental delay. Early treatment with a phenylalanine-restricted diet enables healthy development.

Population Frequencies Across Ancestries

The p.Arg408Trp mutation shows a distinct geographic distribution across ancestral groups. It is especially prevalent in Eastern, Northern, and Central European populations. In several Eastern European and Baltic cohorts, including Poland, Lithuania, and Russia, it accounts for 50% to 75% of all disease-causing PAH alleles identified in PKU cases. In general population datasets such as gnomAD, its minor allele frequency across diverse global groups is roughly 0.0005 to 0.001, rising to approximately 0.005 in European-ancestry populations. Conversely, the variant is exceptionally rare or undetectable in individuals of African, East Asian, and Native American ancestries, where other distinct pathogenic PAH variants are predominantly observed.

What You Can and Cannot Do with This Information

Identifying your genotype at rs5030870 or rs5030858 provides useful insight into personal carrier status and family planning, but it comes with clear limitations. Carrying one copy indicates carrier status for autosomal recessive PKU. If both biological parents are carriers of a pathogenic PAH variant, there is a 25% chance in each pregnancy of having an affected child. A certified genetic counselor can assist with preconception screening and reproductive options. However, a single SNP result cannot definitively rule out carrier status, as more than 1,000 distinct disease-causing variants exist across the PAH gene. Furthermore, educational genetic data is not a diagnostic tool and cannot replace formal newborn metabolic screening or diagnostic clinical sequencing.

Frequently asked questions

Sources & further reading

Related variants in PAH