PAH rs74315447: Understanding the c.1066-11G>A Variant
The rs74315447 variant, also known as c.1066-11G>A, is a genetic change in the PAH gene that affects how the body processes the amino acid phenylalanine. It is recognized as a pathogenic variant frequently associated with phenylketonuria (PKU), a condition that requires careful dietary management.
What each genotype means
Typical PAH enzyme function
This genotype represents the common, functional version of the PAH gene. Individuals with this profile do not carry the specific splice-donor site variant associated with reduced phenylalanine hydroxylase activity.
This is the most common genotype found in the general population across all ancestries.
Carrier of PAH variant
This individual carries one copy of the c.1066-11G>A variant, also known as IVS10nt-11. As an autosomal recessive condition, carriers typically do not exhibit symptoms of phenylketonuria (PKU) but may pass the variant to their offspring.
This genotype is observed in approximately 0.6% to 1.0% of individuals of European non-Finnish ancestry.
Increased risk of PKU
This genotype indicates the presence of two copies of the c.1066-11G>A variant, which is known to disrupt normal PAH gene splicing and reduce enzyme activity. This profile is associated with phenylketonuria (PKU) or hyperphenylalaninemia, and individuals should consult with a metabolic specialist or genetic counselor regarding clinical management.
This genotype is rare in the general population, occurring in approximately 2.6% of identified PKU cases in certain European cohorts.
What is the rs74315447 Variant?
The rs74315447 variant is a specific change in the DNA sequence of the PAH gene, located in intron 10. In genetic literature, it is commonly referred to as c.1066-11G>A or by its legacy name, IVS10nt-11. This variant is classified as a splice-site mutation. Normally, the body uses precise instructions to "splice" or join together segments of genetic code to create a functional protein. Because this variant occurs at a splice-donor site, it interferes with the normal processing of the PAH gene's instructions. Specifically, it can lead to the insertion of extra, incorrect genetic material into the mature messenger RNA (mRNA). This disruption often results in a non-functional or significantly less active version of the phenylalanine hydroxylase enzyme, which is critical for breaking down the amino acid phenylalanine found in many foods.
The Role of the PAH Gene
The PAH gene provides the instructions for making the enzyme phenylalanine hydroxylase. This enzyme is primarily active in the liver and is responsible for converting phenylalanine into another amino acid called tyrosine. Tyrosine is a building block for important neurotransmitters and other essential molecules in the body. When the PAH gene contains pathogenic variants, the resulting enzyme may be absent, unstable, or unable to perform this conversion efficiently. If phenylalanine is not broken down, it can accumulate to toxic levels in the blood and brain. This accumulation is the hallmark of phenylketonuria (PKU). Because the body relies on this enzyme to maintain safe levels of phenylalanine, variations in the PAH gene are the primary focus of newborn screening programs worldwide, which aim to identify infants who may need early dietary intervention to prevent health complications.
Research and Clinical Significance
Research has firmly established rs74315447 as a pathogenic variant in the context of PKU. Clinical databases, including ClinGen, classify this variant as pathogenic based on established criteria, such as its presence in individuals with the condition and its known impact on protein function. It is often referred to as a "Mediterranean mutation" due to its higher prevalence in Southern European populations. Studies indicate that the variant causes an aberrant in-frame insertion of nine nucleotides, which adds three extra amino acids to the protein structure. While the severity of PKU can vary depending on the specific combination of variants an individual carries, this variant is a well-documented marker used in carrier screening. It is important to note that clinical outcomes are complex; individuals often carry two different variants (compound heterozygosity), and the interaction between these variants can influence the overall level of residual enzyme activity.
Population Frequency
The frequency of the rs74315447 variant varies significantly by geography and ancestry. It is notably common in Southern Europe, the Middle East, and parts of Latin America. In some populations, it accounts for a substantial percentage of all identified PAH mutant alleles. For example, it has been reported as a frequent variant in countries like Iran, Turkey, and Spain. In contrast, its frequency in other global populations, such as those of non-Finnish European descent, is generally lower, often estimated in the range of 0.003 to 0.005 in large-scale databases like gnomAD. These differences highlight the importance of considering ancestral background when interpreting genetic screening results, as the prevalence of specific variants is rarely uniform across the globe.
Managing Genetic Information
If you or a family member have been identified as a carrier of the rs74315447 variant, it is important to understand what this means in a clinical context. Being a carrier typically means you have one copy of the variant and one functional copy of the gene, which usually does not result in symptoms of PKU. However, if both parents are carriers, there is a chance of passing the condition to their children. This information is most useful for family planning and understanding personal health history. It is not a diagnosis of a condition. If you have questions about your genetic status, carrier screening results, or the implications for your family, you should consult with a certified genetic counselor or a medical professional. They can provide personalized guidance based on your specific results and family history, ensuring you have the most accurate information for your health decisions.
How common is this variant?
The rs74315447 variant is most prevalent in Southern European, Middle Eastern, and Latin American populations, while appearing at a lower frequency of approximately 0.003 to 0.005 in non-Finnish European populations.
Frequently asked questions
What is the rs74315447 variant?
The rs74315447 variant is a specific genetic change in the PAH gene, also known as c.1066-11G>A. It is a splice-site mutation that can interfere with the production of the enzyme needed to break down phenylalanine.
Is rs74315447 the same as PKU?
No, the variant is a genetic marker associated with the risk of developing phenylketonuria (PKU). PKU is a condition caused by having two pathogenic variants in the PAH gene, which may include rs74315447.
What should I do if I am a carrier of this variant?
Being a carrier means you have one copy of the variant, which typically does not cause health issues. You should discuss your results with a genetic counselor to understand the implications for family planning.
How common is this variant?
Its frequency varies by ancestry, being relatively common in Southern Europe and the Middle East. In many other populations, it is considered rare.
Can this variant be treated?
The variant itself is a permanent part of your DNA and cannot be changed. However, the condition it is associated with, PKU, is managed through specialized dietary restrictions to control phenylalanine levels.
Sources & further reading
Educational information only, last refreshed 10/15/2026. 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.
Missense variant (c.1222C>T, p.Arg408Trp) that disrupts phenylalanine hydroxylase activity, associated with phenylketonuria.
Missense variant (p.Arg408Trp) causing severe classic phenylketonuria (PKU) when inherited bi-allelically due to profound loss of phenylalanine hydroxylase activity.
Splice donor variant (c.1066-11G>A) associated with severe phenylalanine hydroxylase deficiency and phenylketonuria.