PAH rs5030858: Understanding the Arg408Trp Variant
The rs5030858 variant, also known as p.Arg408Trp, is a specific change in the PAH gene that affects the body's ability to process the amino acid phenylalanine. It is primarily studied for its role as a pathogenic variant associated with phenylketonuria (PKU), an autosomal recessive metabolic condition.
What each genotype means
Typical enzyme activity
This genotype indicates you carry two copies of the reference allele, which is associated with normal production and function of the phenylalanine hydroxylase enzyme. This enzyme is responsible for the normal metabolism of the amino acid phenylalanine.
This is the most common genotype across all global populations.
Carrier status for PAH deficiency
You carry one copy of the pathogenic T allele and one copy of the typical C allele. Research indicates that carriers of this variant typically do not experience symptoms of phenylketonuria (PKU), as the single functional copy of the gene is generally sufficient to maintain normal phenylalanine metabolism.
Carried by roughly 1 in 100 to 1 in 200 people of European ancestry, though prevalence varies significantly by specific regional populations.
Potential for PAH deficiency
You carry two copies of the T allele. This variant is a well-established cause of classic phenylketonuria (PKU), a condition characterized by significantly reduced or absent phenylalanine hydroxylase activity. Individuals with this genotype should discuss the clinical implications and appropriate management or testing with their clinician, as it is associated with a high risk for impaired phenylalanine metabolism.
This is a rare genotype in the general population, primarily observed in individuals diagnosed with PKU.
What is rs5030858?
The variant rs5030858 is a single nucleotide polymorphism (SNP) located within the PAH gene on chromosome 12. In scientific literature, this specific change is often referred to as c.1222C>T or p.Arg408Trp (R408W). This notation indicates that at position 408 of the phenylalanine hydroxylase protein, the amino acid arginine is replaced by tryptophan. This change occurs in the catalytic domain of the enzyme, which is the region responsible for the protein's primary chemical activity. Because this alteration occurs in a critical part of the enzyme, it can significantly impact the protein's structure and function. Researchers track this variant because it is one of the most frequently identified genetic changes in individuals diagnosed with phenylketonuria, particularly in populations across Eastern and Northern Europe.
The Role of the PAH Gene
The PAH gene provides the essential instructions for the body to produce an enzyme called phenylalanine hydroxylase. This enzyme acts as a biological catalyst, responsible for breaking down phenylalanine, an amino acid found in many protein-rich foods like meat, eggs, and dairy, as well as in certain artificial sweeteners. Under normal conditions, phenylalanine hydroxylase converts phenylalanine into another amino acid called tyrosine. When the PAH gene contains variants that disrupt this process, phenylalanine cannot be processed efficiently. If left unmanaged, this leads to an accumulation of phenylalanine in the blood and tissues. High levels of this amino acid are toxic to the nervous system, which is why the function of the PAH gene is so critical for normal metabolic health and development.
Research and Clinical Associations
Research has firmly established that rs5030858 is a pathogenic variant associated with phenylketonuria (PKU). PKU is an autosomal recessive disorder, meaning that an individual typically needs to inherit two copies of a pathogenic variant—one from each parent—to manifest the condition. Because rs5030858 reduces the activity of the phenylalanine hydroxylase enzyme, individuals who are homozygous for this variant (carrying two copies) are at a high risk of developing classic PKU. The evidence for this association is strong, as it is one of the most common variants identified in clinical databases like ClinVar. However, it is important to note that the clinical presentation of PKU can vary depending on the specific combination of variants an individual carries. Genetic testing for this variant is often used in the context of carrier screening or diagnostic evaluation for metabolic disorders.
Understanding Your Results
If you have received information about your status for rs5030858, it is important to understand what this means in a clinical context. Being a carrier (having one copy of the variant) generally does not cause symptoms of PKU, as the body typically has enough functional enzyme activity from the other copy of the gene to process phenylalanine. However, if you are concerned about your genetic status or family history, this information should be discussed with a qualified healthcare provider or a genetic counselor. They can provide context based on your specific health history and explain the implications for family planning. This information is for educational purposes and should not be used to diagnose or treat any medical condition. Always consult with a clinician or pharmacist before making any decisions regarding your health or medical management.
How common is this variant?
The rs5030858 variant is relatively rare in the general population, with a minor allele frequency of approximately 0.005 to 0.01 in non-Finnish European populations according to gnomAD data.
Frequently asked questions
What is the relationship between rs5030858 and PKU?
The rs5030858 variant is a known pathogenic mutation in the PAH gene that reduces the activity of the phenylalanine hydroxylase enzyme. Inheriting two copies of this variant is a primary cause of classic phenylketonuria (PKU).
Does having one copy of rs5030858 mean I have PKU?
No, PKU is an autosomal recessive condition, which typically requires two copies of a pathogenic variant to manifest. Having one copy makes you a carrier, which generally does not result in the symptoms of PKU.
How common is the rs5030858 variant?
The variant is relatively uncommon in the general population. In European populations, the allele frequency is generally reported between 0.5% and 1%.
Should I be tested for this variant?
Genetic testing is usually recommended by healthcare providers if there is a family history of PKU or if you are undergoing carrier screening. You should discuss the necessity and implications of such testing with a genetic counselor or your primary care physician.
Sources & further reading
Educational information only, last refreshed 9/24/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Pathogenic missense variant (p.Arg408Trp) associated with phenylketonuria (PKU).
Pathogenic phenylalanine hydroxylase variant conferring risk of phenylketonuria.
A severe pathogenic missense variant (p.Arg408Trp) in the PAH gene associated with phenylketonuria.
Splice-site variant (c.1066-11G>A) causing phenylalanine hydroxylase deficiency.
Splice donor variant (c.1066-11G>A) associated with severe phenylalanine hydroxylase deficiency and phenylketonuria.
Missense variant (p.Arg408Trp) causing severe classic phenylketonuria (PKU) when inherited bi-allelically due to profound loss of phenylalanine hydroxylase activity.