What you carry at this position in your DNA and what research says about it.
Phenylketonuria Risk: 9/10 evidence, 7 publications.
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Sample genotype (not yours): G/G
Typical Phenylketonuria Risk
Normal enzyme activity prevents the buildup of phenylalanine. No increased risk of phenylketonuria is present.
What this genotype means: Typical enzyme function; Normal phenylalanine levels.
Sample genotype (not yours): A/A
High Risk of Phenylketonuria
Two copies of the mutation lead to a severe deficiency in breaking down phenylalanine. This causes classic phenylketonuria, requiring a strict low-protein diet.
What this genotype means: Classic phenylketonuria; Severe enzyme deficiency; High blood phenylalanine levels.
Sample genotype (not yours): G/A
Phenylketonuria Carrier
One copy of the mutation is present, making you a healthy carrier. Phenylalanine levels are typically normal, but the mutation can be passed to children.
What this genotype means: Carrier of PKU mutation; Slightly reduced enzyme activity.
Gene function and biological role
Gene Function: The PAH gene provides instructions for making the enzyme phenylalanine hydroxylase, which is essential for breaking down the amino acid phenylalanine [1]. This enzyme converts phenylalanine into tyrosine, a precursor for key neurotransmitters and melanin pigment [2]. When the PAH gene is mutated, the enzyme cannot function properly, leading to a toxic accumulation of phenylalanine in the blood and brain [1]. This buildup can cause severe intellectual disability, seizures, and developmental delays if left untreated [2].
Variant Impact: The p.Arg408Trp (R408W) missense mutation in exon 12 of the PAH gene replaces the amino acid arginine with tryptophan [3]. This specific change causes severe conformational instability and impairs the molecular motions of the phenylalanine hydroxylase enzyme [1]. As a result, the enzyme is almost completely inactive, retaining less than two percent of its normal function [2]. It is the most common and widely distributed mutation causing classic phenylketonuria in European populations [3].
Key Insight: This variant is the most common cause of classic phenylketonuria in European populations, reducing enzyme activity to less than two percent.
Location: PAH. Chromosome 12 · 12q23.2 · 102.8 Mb
Estimated prevalence by population
Global 99.8%; European 99.7%; African > 99.9%; East Asian 100.0%; South Asian 100.0%; Americas > 99.9%; Ashkenazi 99.9%; Finnish 99.9%; Middle Eastern 100.0%; Amish 100.0%.
Estimated GG genotype frequency.
Global 0.2%; European 0.3%; African < 0.1%; East Asian 0.0%; South Asian 0.0%; Americas < 0.1%; Ashkenazi 0.1%; Finnish 0.1%; Middle Eastern 0.0%; Amish 0.0%.
Estimated GA genotype frequency.
Global < 0.1%; European < 0.1%; African < 0.1%; East Asian 0.0%; South Asian 0.0%; Americas < 0.1%; Ashkenazi < 0.1%; Finnish < 0.1%; Middle Eastern 0.0%; Amish 0.0%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Rare Genetic Disorders
Inherited Metabolic Disorders
Phenylketonuria. Evidence: 9/10. Source: PMID 25596310. Typical Risk.
PAH Enzyme Activity. Evidence: 9/10. Source: PMID 18538294. Typical Activity.
Nutrition & Metabolism
Blood Chemistry & Metabolites
Phenylalanine Levels. Evidence: 8/10. Source: PMID 35213538. Typical Levels.
Showing effects for A/A genotype
Phenylketonuria. Evidence: 9/10. Source: PMID 25596310. High Risk.
PAH Enzyme Activity. Evidence: 9/10. Source: PMID 18538294. Severe Deficiency.
Phenylalanine Levels. Evidence: 8/10. Source: PMID 35213538. Extremely High.
Showing effects for G/A genotype
Phenylketonuria. Evidence: 9/10. Source: PMID 25596310. Carrier Status.
PAH Enzyme Activity. Evidence: 9/10. Source: PMID 18538294. Reduced Activity.
Phenylalanine Levels. Evidence: 8/10. Source: PMID 35213538. Slightly Elevated.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Normal enzyme function is maintained with two copies of the typical G allele [1]. This allows the body to efficiently break down phenylalanine from dietary protein into tyrosine [1]. Consequently, blood levels of phenylalanine remain within the safe, typical range [2]. There is no risk of developing phenylketonuria or passing this specific mutation to offspring [1]. Standard dietary choices and protein intake do not pose any genetic health concerns at this locus [2]. The body easily processes common protein-rich foods like meat, dairy, and nuts without metabolic strain. No special dietary restrictions or medical interventions are required for this genotype. Overall metabolic health regarding phenylalanine clearance is fully preserved.
Typical enzyme function; Normal phenylalanine levels.
Sample genotype: AA (Homozygous)
Severe enzyme deficiency occurs when two copies of the A allele are present, resulting in a near-complete loss of phenylalanine hydroxylase activity [1]. Without functional enzymes, phenylalanine from dietary protein rapidly accumulates to toxic levels in the blood and brain [2]. This severe metabolic condition, known as classic phenylketonuria, can cause irreversible brain damage and intellectual disability if untreated [1]. Fortunately, early diagnosis through newborn screening and a lifelong low-phenylalanine diet prevent these severe neurological complications [2]. Management involves avoiding high-protein foods like meat, dairy, and artificial sweeteners containing aspartame [1]. Specialized medical formulas are used to provide essential amino acids without phenylalanine. Regular blood monitoring helps ensure levels remain within a safe therapeutic range. Modern medical advancements continue to improve treatment options and quality of life for affected individuals.
Classic phenylketonuria; Severe enzyme deficiency; High blood phenylalanine levels.
Sample genotype: GA (Heterozygous)
A single copy of the A allele reduces overall phenylalanine hydroxylase enzyme activity, but the remaining healthy copy is sufficient to prevent classic symptoms [1]. Although some carriers may show slightly higher blood phenylalanine levels under metabolic stress, they do not develop phenylketonuria [2]. This status is clinically considered benign for the individual's own health [1]. However, there is a fifty percent chance of passing this mutation to offspring [1]. If a partner is also a carrier, future children face a twenty-five percent risk of inheriting phenylketonuria [1]. Genetic counseling is often recommended for carriers planning a family to assess partner status. No dietary restrictions or special medical treatments are necessary for daily life. General health and cognitive development remain completely unaffected by this carrier status.
Carrier of PKU mutation; Slightly reduced enzyme activity.
Variants with shared genetic architecture
rs199475575 · PAH Gene · Chr 12 · Phenylketonuria Risk
rs5030847 · PAH Gene · Chr 12 · Phenylketonuria Risk
rs5030850 · PAH Gene · Chr 12 · Phenylketonuria Risk
Content updated August 2026.
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