What you carry at this position in your DNA and what research says about it.
Ammonia Clearance: 7/10 evidence, 9 publications.
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Sample genotype (not yours): G/G
Optimal Ammonia Clearance and Urea Cycle Function
Two normal copies of the gene ensure fully functional enzyme levels. Ammonia is efficiently processed and cleared from the body.
What this genotype means: Normal ammonia clearance; Typical protein tolerance.
Sample genotype (not yours): A
Severe Ornithine Transcarbamylase Deficiency Risk
A single variant copy of the gene on the X chromosome causes severe enzyme deficiency. This leads to a high risk of dangerous ammonia buildup and requires immediate medical management.
What this genotype means: Severe ammonia clearance deficiency; High risk of hyperammonemia; Requires low-protein diet.
Sample genotype (not yours): A/A
High Risk of Ornithine Transcarbamylase Deficiency
Two copies of the variant allele cause severe enzyme deficiency. This leads to a high risk of ammonia buildup, requiring medical management and dietary protein restriction.
Sample genotype (not yours): G
A single normal copy of the gene on the X chromosome ensures fully functional enzyme levels. Ammonia is efficiently processed and cleared from the body.
Sample genotype (not yours): G/A
Healthy Carrier of Urea Cycle Variant
One normal copy and one variant copy typically provide enough enzyme activity for normal health. Extreme metabolic stress or high protein loads may occasionally cause mild symptoms.
What this genotype means: Carrier status; Possible mild protein sensitivity under extreme stress.
Gene function and biological role
Gene Function: The OTC gene encodes ornithine transcarbamylase, a critical mitochondrial enzyme in the urea cycle [1]. This cycle is the primary metabolic pathway used by the liver to convert toxic ammonia, a byproduct of protein breakdown, into urea for excretion in urine [1]. When this enzyme is deficient or malfunctioning, ammonia accumulates in the bloodstream, leading to hyperammonemia [2]. Severe deficiency of this enzyme is the most common inherited urea cycle disorder in humans [2]. This pathway is essential for preventing nitrogen toxicity in the central nervous system.
Variant Impact: The rs66656800 variant is a missense mutation that changes the amino acid arginine to histidine at position 129 of the ornithine transcarbamylase enzyme [3]. This specific change, often referred to as p.Arg129His, significantly reduces the enzyme's catalytic activity [3]. In laboratory models and human cases, this mutation is associated with a dramatic reduction in functional enzyme levels, sometimes leaving less than five percent of normal activity [4]. The resulting impairment in the urea cycle leads to a high risk of ammonia buildup, particularly after high-protein meals or during periods of metabolic stress [3]. This particular variant is well-documented in medical literature as a cause of both early-onset and late-onset deficiency symptoms.
Key Insight: A single variant copy of this gene can cause severe symptoms in males, while females with one copy are typically healthy carriers due to having a second X chromosome.
Location: OTC. Chromosome X · Xp11.4 · 38.4 Mb
Estimated prevalence by population
No frequency data available
This variant is not present in the gnomAD database.
Showing effects for G/G genotype
Rare Genetic Disorders
Inherited Metabolic Disorders
Ammonia Clearance. Evidence: 7/10. Source: PMID 24006547. Typical Clearance.
Protein Tolerance. Evidence: 7/10. Source: PMID 24006547. Typical Tolerance.
Organ Systems
Liver Function & Disease
Liver Health. Evidence: 7/10. Source: PMID 27070778. Typical Risk.
Neurology & Mental Health
Neurodegenerative Diseases
Neurological Health. Evidence: 7/10. Source: PMID 24006547. Typical Risk.
Showing effects for A genotype
Ammonia Clearance. Evidence: 7/10. Source: PMID 24006547. Severely Reduced.
Protein Tolerance. Evidence: 7/10. Source: PMID 24006547. Low Tolerance.
Liver Health. Evidence: 7/10. Source: PMID 27070778. High Risk of Failure.
Neurological Health. Evidence: 7/10. Source: PMID 24006547. High Risk of Damage.
Showing effects for A/A genotype
Showing effects for G genotype
Showing effects for G/A genotype
Ammonia Clearance. Evidence: 7/10. Source: PMID 24006547. Slightly Reduced.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Having two copies of the normal G allele provides the body with fully functional ornithine transcarbamylase enzymes [1]. The liver can seamlessly process nitrogen waste from dietary protein, preventing any toxic accumulation of ammonia in the bloodstream [1]. This optimal enzyme activity protects against metabolic crises, liver complications, and neurological symptoms associated with urea cycle disorders [2]. No dietary restrictions or special precautions regarding protein intake are necessary based on this genetic marker [1]. The body is fully capable of handling typical protein loads from a standard diet. Physical exertion, fasting, and common illnesses do not pose any unusual metabolic risks. Overall, this genotype represents the standard, healthy baseline for urea cycle function.
Normal ammonia clearance; Typical protein tolerance.
Sample genotype: A (Single copy)
Having a single variant A allele on the X chromosome results in a severe deficiency of the ornithine transcarbamylase enzyme because males have only one X chromosome [1]. Without functional enzymes, the liver cannot properly convert toxic ammonia into urea, leading to dangerous ammonia accumulation in the blood [1]. This condition can cause recurrent episodes of vomiting, lethargy, and acute liver failure, especially during metabolic stress or illness [2]. Management typically involves a strict low-protein diet, specialized amino acid supplements, and close medical supervision to prevent neurological complications [1]. Early diagnosis and proactive treatment are essential to avoid long-term developmental or neurological damage. Families often work closely with metabolic specialists and dietitians to create safe, customized nutrition plans. In severe cases, advanced medical therapies or liver transplantation may be considered to restore normal metabolic function.
Severe ammonia clearance deficiency; High risk of hyperammonemia; Requires low-protein diet.
Sample genotype: AA (Homozygous)
Carrying two copies of the variant A allele results in a severe deficiency of the ornithine transcarbamylase enzyme [1]. Without functional enzymes, the liver cannot properly convert toxic ammonia into urea, leading to dangerous ammonia accumulation in the blood [1]. This condition can cause recurrent episodes of vomiting, lethargy, and acute liver failure, especially during metabolic stress or illness [2]. Management typically involves a strict low-protein diet, specialized amino acid supplements, and close medical supervision to prevent neurological complications [1]. Early diagnosis and proactive treatment are essential to avoid long-term developmental or neurological damage. Families often work closely with metabolic specialists and dietitians to create safe, customized nutrition plans. In severe cases, advanced medical therapies or liver transplantation may be considered to restore normal metabolic function.
Sample genotype: G (Single copy)
Having a single normal G allele on the X chromosome provides fully functional ornithine transcarbamylase enzymes [1]. The liver can seamlessly process nitrogen waste from dietary protein, preventing any toxic accumulation of ammonia in the bloodstream [1]. This optimal enzyme activity protects against metabolic crises, liver complications, and neurological symptoms associated with urea cycle disorders [2]. No dietary restrictions or special precautions regarding protein intake are necessary based on this genetic marker [1]. The body is fully capable of handling typical protein loads from a standard diet. Physical exertion, fasting, and common illnesses do not pose any unusual metabolic risks. Overall, this genotype represents the standard, healthy baseline for urea cycle function.
Sample genotype: GA (Heterozygous)
Carrying one normal G allele and one variant A allele typically results in a healthy carrier state because the normal copy produces sufficient enzyme activity for daily life [1]. However, because of X-chromosome inactivation, some liver cells may express only the mutant enzyme, which can occasionally lead to mild biochemical changes like elevated urinary orotic acid [2]. Under normal circumstances, carriers do not experience symptoms, but extreme metabolic stress, prolonged fasting, or massive protein intake can sometimes trigger mild fatigue or headaches [1]. Maintaining a balanced diet and avoiding extreme high-protein regimens is generally recommended as a sensible precaution [1]. Regular medical checkups can help monitor liver function and general metabolic health over time. Most individuals with this genotype lead completely normal, active lives without any clinical intervention. It is important to share this carrier status with family members, as it can be passed on to offspring.
Carrier status; Possible mild protein sensitivity under extreme stress.
Variants with shared genetic architecture
rs66642398 · OTC Gene · Chr X · Urea Cycle Function
rs66724222 · OTC Gene · Chr X · Urea Cycle Function
rs67294955 · OTC Gene · Chr X · Ammonia Detoxification
Ornithine Transcarbamylase Deficiency.
Content updated August 2026.
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