COMT rs165599: Understanding This Stress-Related Genetic Variant
The rs165599 variant is a single nucleotide polymorphism located in the COMT gene, which plays a role in regulating dopamine levels in the brain. Research suggests this variant may influence how individuals respond to stress and its subsequent impact on cognitive performance.
What each genotype means
Typical baseline catecholamine regulation
You carry two copies of the A allele at rs165599. In preliminary research, this genotype has been linked to higher expression of COMT mRNA compared to G-allele carriers, though evidence regarding overall stress reactivity and cognitive performance is mixed and limited. These findings represent broad population associations rather than a clinical diagnosis, and actual cognitive and emotional outcomes depend heavily on lifestyle and environment.
Carried by approximately 25% to 45% of individuals of European ancestry, and is frequent globally.
Intermediate catecholamine expression profile
You carry one copy of the A allele and one copy of the G allele at rs165599. Research suggests this heterozygous genotype may confer intermediate COMT expression, potentially influencing how prefrontal cortical circuits process stress and cognitive tasks. However, scientific evidence linking this non-coding variant directly to distinct behavioral changes remains limited and context-dependent.
Carried by roughly 45% to 50% of individuals in European and many global populations.
Altered stress and cognitive sensitivity
You carry two copies of the G allele at rs165599. Some studies have associated the G allele with modestly reduced COMT mRNA expression in brain tissue and altered susceptibility to environmental stress during neurodevelopment. Because the clinical evidence is limited and often variable across ancestries, this genotype does not determine medical outcomes or psychiatric risk on its own.
Found in roughly 10% to 20% of people of European ancestry, with varying frequencies across other global populations.
What is rs165599?
The rs165599 variant is a single nucleotide polymorphism (SNP) found within the catechol-O-methyltransferase (COMT) gene. Unlike variants that change the structure of a protein, rs165599 is a non-coding variant, meaning it sits in a region of the gene that does not directly code for the amino acid sequence of the COMT enzyme. Instead, such variants are often investigated for their potential to influence gene expression—how much of the protein is produced or when it is activated. Because it is located in a regulatory region, researchers study it to see if it modulates the efficiency of catecholamine degradation in the prefrontal cortex, a brain region critical for executive functions like working memory, planning, and emotional regulation.
The Role of the COMT Gene
The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. This enzyme is responsible for breaking down neurotransmitters known as catecholamines, which include dopamine, epinephrine, and norepinephrine. In the prefrontal cortex, dopamine levels must be tightly regulated to support optimal cognitive function. If the COMT enzyme is too active, it may break down dopamine too quickly; if it is less active, dopamine may persist longer in the synaptic space. Because rs165599 is associated with the COMT gene, scientists hypothesize that it may indirectly influence the availability of these neurotransmitters, potentially altering how the brain processes information, especially under conditions of high stress or cognitive demand.
Research and Evidence Strength
The evidence linking rs165599 to specific health outcomes is currently considered limited and mixed. Some studies have explored its role in psychiatric conditions, such as schizophrenia, but meta-analyses have often failed to find a consistent, direct association across diverse populations. Other research has focused on gene-environment interactions, such as a study suggesting that the G allele might influence how maternal stress during pregnancy affects a child's IQ. While these findings are intriguing, they highlight the complexity of genetics; a single variant rarely acts in isolation. Because results vary significantly between studies and populations, the scientific community views these associations as preliminary rather than definitive markers for predicting individual cognitive or psychiatric outcomes.
Interpreting Your Genetic Information
It is important to understand that genetic variants like rs165599 do not determine your future or your cognitive abilities. Human traits are polygenic, meaning they are influenced by hundreds or thousands of variants, as well as significant environmental and lifestyle factors. If you have received information about your rs165599 genotype, it should be viewed as a small piece of a much larger, complex puzzle. This information is not a diagnostic tool and cannot predict how you will perform on cognitive tasks or how you will respond to stress. If you have concerns about your mental health, cognitive function, or stress management, please consult with a qualified healthcare professional who can provide personalized guidance based on your full clinical history.
How common is this variant?
The rs165599 variant is common, with a minor allele frequency of approximately 0.46 in European populations according to gnomAD data.
Frequently asked questions
Is rs165599 a cause of schizophrenia?
No. Meta-analyses have shown that rs165599 is not a single-risk factor for schizophrenia. While some early studies suggested a link, larger reviews have not found a consistent association.
Can I use this SNP to predict my IQ?
No. IQ is a complex trait influenced by many genetic and environmental factors. This SNP is not a reliable predictor of intelligence or cognitive performance.
Does this variant affect how I handle stress?
Some research suggests a potential interaction between this variant and stress, but the evidence is limited. It is not a definitive indicator of how an individual will respond to stressful situations.
Should I change my lifestyle based on my rs165599 genotype?
No. You should not make health or lifestyle changes based on this variant. Always consult with a healthcare provider for personalized medical advice.
Sources & further reading
Educational information only, last refreshed 10/18/2026. Not medical advice — these associations describe population statistics, not individual predictions.
Curious what your genotype is for rs165599?
Upload a raw DNA file from 23andMe, AncestryDNA, MyHeritage, or FamilyTreeDNA and see this variant — plus thousands more — interpreted in your full report.
Get my report — $29Related variants in COMT
Intronic regulatory polymorphism in COMT linked in haplotype studies to altered dopamine turnover and executive function.
Part of the central COMT haploblock regulating catecholamine breakdown and modifying pain sensitivity profiles.
Synonymous variant in COMT in linkage disequilibrium with Val158Met, influencing enzyme stability and pain sensitivity.
COMT Val158Met ('warrior/worrier') variant affecting dopamine tone and stress resilience.
A synonymous variant in the COMT gene that acts in linkage with Val158Met to influence enzyme stability and pain sensitivity.
Intronic tag SNP in linkage disequilibrium with functional catechol-O-methyltransferase activity variations, frequently studied in pain perception and neuropsychiatric endophenotypes.