SERPINA1 rs28929470: Understanding the Z Allele and AAT Deficiency
The rs28929470 variant in the SERPINA1 gene, commonly known as the Z allele, is a well-studied genetic change associated with alpha-1 antitrypsin deficiency. This condition can lead to reduced levels of a protective protein, potentially increasing the risk of lung and liver disease.
What each genotype means
Severe deficiency risk
This genotype is associated with the Pi*Z pathogenic allele, which can lead to severe alpha-1 antitrypsin deficiency. Individuals with this profile may have an increased risk for lung emphysema and liver disease due to protein misfolding. Please discuss these results and any necessary clinical monitoring with your healthcare provider.
This genotype is rare in the general population, with the Pi*Z allele frequency estimated at approximately 1-3% in European populations.
Carrier status
This genotype indicates you carry one copy of the Pi*Z variant. While typically associated with a milder reduction in alpha-1 antitrypsin levels compared to having two copies, it is important to discuss your health history and potential risks for lung or liver conditions with a clinician.
Carried by a small percentage of individuals of European ancestry, reflecting the 1-3% frequency of the Pi*Z allele in these populations.
Complex deficiency risk
This genotype involves the Pi*Z allele alongside another variant, which may influence alpha-1 antitrypsin protein levels. The clinical significance can vary based on the specific interaction of these alleles, so you should consult with a genetic counselor or physician to understand your specific health implications.
This specific combination is rare and depends on the local prevalence of the Pi*Z allele and other SERPINA1 variants.
Typical risk profile
This genotype represents the common, functional version of the SERPINA1 gene, often referred to as the Pi*M allele. It is not associated with the severe alpha-1 antitrypsin deficiency linked to the Pi*Z variant.
This is the most common genotype found in the general population.
Typical risk profile
This genotype contains the common functional allele and a secondary variant. It is generally not associated with the severe deficiency seen in Pi*Z homozygotes, but you should consult a clinician if you have concerns about your alpha-1 antitrypsin levels.
This genotype is relatively common, reflecting the background variation of the SERPINA1 gene in the general population.
Severe deficiency risk
This genotype is associated with the Pi*Z pathogenic allele, which can lead to severe alpha-1 antitrypsin deficiency. Individuals with this profile may have an increased risk for lung emphysema and liver disease due to protein misfolding. Please discuss these results and any necessary clinical monitoring with your healthcare provider.
This genotype is rare in the general population, with the Pi*Z allele frequency estimated at approximately 1-3% in European populations.
What is rs28929470?
The variant rs28929470 is a specific change in the DNA sequence of the SERPINA1 gene, located on chromosome 14. In scientific literature, this variant is famously referred to as the Z allele. It involves a single nucleotide substitution that results in a change to the amino acid sequence of the alpha-1 antitrypsin protein. This alteration is significant because it affects how the protein folds and functions within the body. Because the SERPINA1 gene provides the blueprint for this essential protein, changes like rs28929470 can have downstream effects on the body's ability to regulate certain enzymes. It is one of the most clinically relevant variants identified in the study of genetic predispositions to respiratory and hepatic conditions.
The Role of the SERPINA1 Gene
The SERPINA1 gene is responsible for producing alpha-1 antitrypsin, a protein that acts as a serine protease inhibitor. Its primary job is to protect tissues, particularly in the lungs, from damage caused by enzymes that break down proteins. When the body produces enough functional alpha-1 antitrypsin, it effectively neutralizes these enzymes, preventing them from harming healthy lung tissue. However, when variants like rs28929470 are present, the resulting protein may be misfolded or produced in insufficient quantities. This leads to a deficiency, where the protective shield for the lungs is weakened. Additionally, the misfolded protein can accumulate in the liver, which may lead to liver-related health issues over time. Understanding this gene is crucial for grasping how genetic variations can influence systemic health.
Research and Clinical Associations
Research has consistently linked the rs28929470 variant to alpha-1 antitrypsin deficiency (AATD). The evidence for this association is strong, as the Z allele is a primary driver of the condition in many populations. Individuals who inherit two copies of this variant (homozygous) are at a significantly higher risk for severe deficiency, which can manifest as pulmonary emphysema or liver disease. Those who carry only one copy (heterozygous) may have intermediate levels of the protein and a potentially lower, though still present, risk. It is important to note that while the association with deficiency is well-established, the clinical outcome for any individual can vary based on environmental factors, such as smoking, which can exacerbate lung damage in those with the deficiency. Clinical diagnosis relies on measuring serum protein levels rather than genetic testing alone.
Population Frequency
The rs28929470 variant is most frequently observed in populations of European descent. Studies indicate that the minor allele frequency typically ranges between 0.01 and 0.02 in these groups. While it is a significant cause of deficiency in these populations, it is considered rare or absent in many other global populations. Large-scale sequencing efforts, such as those found in gnomAD, continue to refine our understanding of how this variant is distributed geographically. Because the frequency is relatively low, it is not a common variant in the general population, but its impact on those who carry it can be profound. Genetic screening programs often focus on regions where the prevalence of this allele is higher to facilitate early detection and management of potential health risks.
Managing Genetic Information
Knowing your status regarding the rs28929470 variant can provide insight into your genetic predisposition, but it is not a medical diagnosis. If you have concerns about your results or family history, the most important step is to consult with a healthcare professional or a genetic counselor. They can help interpret what these findings mean in the context of your overall health and discuss appropriate clinical testing, such as measuring alpha-1 antitrypsin levels in the blood. This information should not be used to self-diagnose or make changes to your lifestyle without professional guidance. Remember that genetic factors are only one piece of the puzzle; environmental factors and overall health management play a critical role in how these genetic predispositions manifest. Always prioritize evidence-based medical advice over general genetic information.
How common is this variant?
The rs28929470 variant has a minor allele frequency of approximately 0.01 to 0.02 in European populations, where it is most commonly found.
Frequently asked questions
What is the Z allele in SERPINA1?
The Z allele is a specific genetic variant (rs28929470) in the SERPINA1 gene. It is known for causing the protein to misfold, leading to alpha-1 antitrypsin deficiency.
Does having the Z allele mean I have a disease?
Not necessarily. Having the variant indicates a genetic predisposition, but clinical diagnosis requires blood tests to measure protein levels and an evaluation by a doctor.
How is alpha-1 antitrypsin deficiency diagnosed?
Diagnosis is typically confirmed by measuring the concentration of alpha-1 antitrypsin in the blood. Genetic testing may be used to identify the specific variants present.
Can I prevent health issues if I have this variant?
While you cannot change your genetics, you can work with a doctor to manage your health. Avoiding lung irritants like cigarette smoke is often recommended for those with this deficiency.
Sources & further reading
Educational information only, last refreshed 9/21/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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The 'Z' allele (p.Glu366Lys) associated with alpha-1 antitrypsin deficiency.
Rare deficiency null allele (Pi*Null Granite Falls) in SERPINA1 conferring carrier status for severe alpha-1 antitrypsin deficiency.
The Alpha-1-antitrypsin PI*I deficiency missense allele (Arg39Phe) predisposing carriers to reduced serum levels and pulmonary vulnerability.
The Pi*S allele of SERPINA1 that causes mild-to-moderate deficiency of alpha-1 antitrypsin.
Known as the S allele (p.Glu288Val), associated with mild alpha-1 antitrypsin deficiency when compounded with Z alleles.
The Z allele (E342K) of the SERPINA1 gene is the most common cause of severe alpha-1 antitrypsin deficiency.