What you carry at this position in your DNA and what research says about it.
Urea Cycle and Kidney Health: 10/10 evidence, 73 publications.
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Sample genotype (not yours): C/C
Optimal Urea Cycle Function and Better Kidney Filtration
Optimal enzyme activity supports efficient nitrogen clearance and is linked to higher kidney filtration rates and higher HDL cholesterol. However, this efficient state is also associated with slightly higher blood pressure and a higher risk of a rare eye condition.
What this genotype means: Optimal ammonia clearance; Higher kidney filtration rate; Slightly higher blood pressure.
Sample genotype (not yours): A/A
Reduced Enzyme Activity and Lower Kidney Filtration
Reduced enzyme activation leads to less efficient ammonia clearance, lower kidney filtration rates, and lower HDL cholesterol. However, this reduced activity provides a protective effect against high blood pressure and certain eye conditions.
What this genotype means: Reduced urea cycle efficiency; Lower kidney filtration rate; Higher risk of drug-induced hyperammonemia.
Sample genotype (not yours): C/A
Balanced Enzyme Activity with Moderate Metabolic Trade-offs
Intermediate enzyme activity balances efficient ammonia clearance with a moderate risk profile. This genotype is associated with typical kidney filtration rates and standard cholesterol levels, alongside a slight sensitivity to certain medications.
What this genotype means: Moderate urea cycle efficiency; Slightly elevated risk of drug-induced hyperammonemia; Typical kidney filtration.
Gene function and biological role
Gene Function: The CPS1 gene encodes carbamoyl-phosphate synthase 1, a mitochondrial enzyme that catalyzes the first and rate-limiting step of the urea cycle [1]. This critical pathway converts highly toxic ammonia, a byproduct of protein metabolism, into urea for excretion by the kidneys [1]. Beyond ammonia clearance, CPS1 activity indirectly influences the production of nitric oxide, a key regulator of blood vessel dilation and cardiovascular health [2]. Genetic variations that alter CPS1 function can impact systemic nitrogen balance, vascular tone, and lipid metabolism [2] [3].
Variant Impact: The rs1047891 variant is a missense mutation in the CPS1 gene that causes a threonine-to-asparagine amino acid substitution at position 1406 [2]. This structural change occurs within the binding domain for N-acetylglutamate, an essential allosteric activator required for CPS1 enzyme function [2]. The A allele reduces the enzyme's sensitivity to this activator, leading to lower overall urea cycle efficiency and decreased ammonia clearance [2] [4]. Conversely, the ancestral C allele maintains optimal enzyme activation, supporting efficient nitrogen processing but slightly altering downstream metabolic pathways [4] [3].
Key Insight: A single amino acid change in the urea cycle rate-limiting enzyme simultaneously influences kidney filtration rate, HDL cholesterol levels, and blood pressure.
Location: CPS1. Chromosome 2 · 2q34 · 210.7 Mb
Estimated prevalence by population
Global 45.6%; European 46.7%; African 40.2%; East Asian 71.1%; South Asian 49.9%; Americas 47.4%; Ashkenazi 45.5%; Finnish 41.7%; Middle Eastern 49.6%; Amish 43.2%.
Estimated CC genotype frequency.
Global 43.6%; European 43.3%; African 46.4%; East Asian 26.4%; South Asian 41.5%; Americas 42.9%; Ashkenazi 43.9%; Finnish 45.7%; Middle Eastern 41.7%; Amish 45.1%.
Estimated CA genotype frequency.
Global 10.8%; European 10.0%; African 13.4%; East Asian 2.5%; South Asian 8.6%; Americas 9.7%; Ashkenazi 10.6%; Finnish 12.5%; Middle Eastern 8.8%; Amish 11.8%.
Estimated AA genotype frequency.
Showing effects for C/C genotype
Organ Systems
Kidney Function & Disease
Kidney Function. Evidence: 10/10. Source: PMID 34272381. Higher eGFR.
Vision & Eye Health
Macular Telangiectasia. Evidence: 6/10. Source: PMID 33654266. ~1.8x Higher Risk.
Cardiovascular & Metabolic
Lipids & Cholesterol
HDL Cholesterol. Evidence: 10/10. Source: PMID 32203549. Higher HDL.
Hypertension
Blood Pressure. Evidence: 9/10. Source: PMID 38689001. Slightly Higher BP.
Pharmacogenomics
Antiepileptic & Mood-Stabilizer Response
Valproic Acid Response. Evidence: 3/10. Source: PMID 31151073. Typical Risk.
Showing effects for A/A genotype
Kidney Function. Evidence: 10/10. Source: PMID 34272381. Lower eGFR.
Macular Telangiectasia. Evidence: 6/10. Source: PMID 33654266. Lower Risk.
HDL Cholesterol. Evidence: 10/10. Source: PMID 32203549. Lower HDL.
Blood Pressure. Evidence: 9/10. Source: PMID 38689001. Slightly Lower BP.
Valproic Acid Response. Evidence: 3/10. Source: PMID 31151073. Higher Risk.
Showing effects for C/A genotype
Kidney Function. Evidence: 10/10. Source: PMID 34272381. Typical eGFR.
Macular Telangiectasia. Evidence: 6/10. Source: PMID 33654266. Typical Risk.
HDL Cholesterol. Evidence: 10/10. Source: PMID 32203549. Typical HDL.
Blood Pressure. Evidence: 9/10. Source: PMID 38689001. Typical BP.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Optimal carbamoyl-phosphate synthase 1 activity ensures that ammonia is rapidly cleared from the bloodstream and converted to urea [1]. This highly efficient metabolic state is strongly associated with a higher estimated glomerular filtration rate, indicating robust kidney function [2]. Additionally, this genotype is linked to higher circulating levels of protective HDL cholesterol [3]. On the other hand, increased urea cycle flux is associated with slightly elevated systolic and diastolic blood pressure [4]. There is also an increased susceptibility to macular telangiectasia type 2, a rare degenerative disease of the retina [5]. Overall, this genotype represents the fully functional, ancestral state of the enzyme, offering excellent metabolic clearance at the cost of minor cardiovascular and ocular trade-offs.
Optimal ammonia clearance; Higher kidney filtration rate; Slightly higher blood pressure.
Sample genotype: AA (Homozygous)
Two copies of the variant asparagine allele significantly impair the allosteric activation of the carbamoyl-phosphate synthase 1 enzyme [1]. This impairment leads to less efficient nitrogen processing and is associated with a lower estimated glomerular filtration rate, reflecting reduced kidney function [2]. Additionally, this genotype is linked to lower circulating levels of protective HDL cholesterol [3]. Under metabolic stress or when taking the anti-seizure drug valproic acid, the reduced enzyme reserve can lead to a buildup of toxic ammonia in the blood [4]. Conversely, the lower urea cycle flux offers some unique physiological advantages, including a significantly lower risk of developing macular telangiectasia type 2 [5]. It is also associated with slightly lower systolic and diastolic blood pressure, which may offer mild cardiovascular protection [6].
Reduced urea cycle efficiency; Lower kidney filtration rate; Higher risk of drug-induced hyperammonemia.
Sample genotype: CA (Heterozygous)
A single copy of the variant asparagine allele slightly reduces the activation efficiency of the carbamoyl-phosphate synthase 1 enzyme [1]. This intermediate state generally maintains adequate ammonia clearance under normal physiological conditions, resulting in typical kidney filtration rates and standard HDL cholesterol levels [2] [3]. However, the reduction in enzyme reserve makes carriers more sensitive to metabolic stressors [1]. For instance, exposure to the anti-seizure medication valproic acid can significantly inhibit the remaining enzyme activity, increasing the risk of hyperammonemia [4]. On the positive side, the slight reduction in urea cycle flux correlates with a lower risk of macular telangiectasia type 2 and slightly lower blood pressure compared to the C/C genotype [5] [6]. This genotype represents a balanced metabolic middle ground with minor drug-response considerations.
Moderate urea cycle efficiency; Slightly elevated risk of drug-induced hyperammonemia; Typical kidney filtration.
Variants with shared genetic architecture
rs715 · CPS1 Gene · Chr 2 · Heart Disease Risk
rs267738 · CERS2 Gene · Chr 1 · Kidney and Lipid Health
rs3741414 · INHBC Gene · Chr 12 · Metabolic and Kidney Health
Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function.
Content updated August 2026.
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