SERPINA1 rs28929474: Understanding the Z Allele
The rs28929474 variant, commonly referred to as the Z allele of the SERPINA1 gene, is a well-studied genetic change associated with alpha-1 antitrypsin deficiency. Individuals who inherit two copies of this variant may experience significantly reduced levels of a protective protein, which can increase the risk of developing lung and liver conditions.
What each genotype means
Typical alpha-1 antitrypsin levels
This genotype represents the common, functional version of the SERPINA1 gene, often referred to as the M allele. Individuals with this profile typically produce normal levels of the alpha-1 antitrypsin protein, which helps protect the lungs from damage.
This is the most common genotype found in the general population across all ancestries.
Alpha-1 antitrypsin deficiency carrier
This genotype indicates you carry one copy of the Z allele (rs28929474) and one copy of the normal M allele. While you are generally considered a carrier and may have slightly lower levels of the protective protein, research into the health impacts of this heterozygous state is ongoing, particularly regarding potential risks for lung or liver conditions. You should discuss any concerns about your respiratory or liver health with your healthcare provider.
Carried by roughly 1 to 2 percent of individuals of European ancestry.
Alpha-1 antitrypsin deficiency
This genotype indicates two copies of the Z allele, which is the most common cause of severe alpha-1 antitrypsin deficiency. This condition significantly reduces the amount of protective protein in the body, leading to a high risk of developing lung diseases like emphysema and chronic obstructive pulmonary disease (COPD), as well as potential liver disease. It is essential to consult with a medical professional or genetic counselor to discuss clinical monitoring, lifestyle adjustments such as avoiding smoking, and potential therapeutic options.
This is a rare genotype, most frequently observed in individuals of Northern European descent.
What is the rs28929474 Variant?
The rs28929474 variant is a specific change in the DNA sequence of the SERPINA1 gene, located on chromosome 14. In scientific literature, this variant is frequently called the Z allele or the E342K mutation. It involves a single nucleotide substitution that results in an amino acid change from glutamic acid to lysine at position 342 of the alpha-1 antitrypsin protein. This structural alteration causes the protein to misfold and polymerize within the liver cells where it is produced. Because these proteins become trapped inside the liver, they cannot be secreted into the bloodstream in sufficient quantities to perform their protective functions throughout the body. This mechanism is the primary reason why the Z allele is considered a major contributor to deficiency-related health issues.
The Role of the SERPINA1 Gene
The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin (AAT). This protein acts as a protease inhibitor, meaning it protects the body's tissues from damage caused by enzymes released during inflammation. Specifically, AAT is crucial for protecting the lungs from neutrophil elastase, an enzyme that can break down connective tissue if left unchecked. When the SERPINA1 gene functions normally, AAT travels through the blood to the lungs, where it neutralizes these enzymes. However, when the Z allele is present, the resulting AAT protein is unstable and prone to clumping. This leads to two main problems: a lack of protective AAT in the lungs, which can lead to emphysema, and the accumulation of abnormal protein in the liver, which can potentially cause liver damage or disease.
Research and Clinical Associations
Research into rs28929474 is extensive, with strong evidence linking it to alpha-1 antitrypsin deficiency (AATD). Individuals who are homozygous for the Z allele (inheriting one copy from each parent) are at the highest risk for severe deficiency and associated clinical manifestations, such as early-onset emphysema and liver disease. The evidence for this association is considered strong and is well-documented in clinical genetics. Recent studies have also explored the effects of being a heterozygote—carrying only one copy of the Z allele. While heterozygotes generally have higher AAT levels than homozygotes, some research suggests they may still face a slightly increased risk for certain respiratory or liver-related conditions compared to the general population. However, the clinical impact of carrying a single copy remains a subject of ongoing investigation, and not all carriers will experience health complications.
Population Frequency
The Z allele is most commonly found in individuals of Northern European descent. Because it is a recessive trait in terms of severe disease risk, the frequency of the homozygous genotype is relatively low in the general population, while the carrier state is more common. Prevalence estimates for AATD vary, but it is recognized as a significant genetic condition in European populations. It is important to note that genetic risk is only one factor in health outcomes; environmental factors, such as smoking or exposure to air pollution, play a critical role in how the Z allele influences lung function. Because of this, individuals with this variant are often advised to avoid lung irritants to help mitigate potential risks.
What This Information Means for You
Knowing your status for rs28929474 can provide insight into your genetic predisposition for alpha-1 antitrypsin deficiency. If you are concerned about your results or have a family history of lung or liver disease, it is essential to discuss this information with a healthcare professional or a genetic counselor. They can help interpret what your specific genotype means in the context of your overall health and family history. This information is not a medical diagnosis and cannot predict with certainty whether you will develop a condition. If you are currently taking medications or considering treatments, always consult your clinician or pharmacist before making any changes. They can provide personalized guidance based on your clinical profile and the latest medical standards.
How common is this variant?
The Z allele is most prevalent in individuals of Northern European descent. While the carrier state is relatively common in these populations, the homozygous state is much rarer.
Frequently asked questions
What is the difference between being a carrier and having the deficiency?
A carrier (heterozygote) has one copy of the Z allele and one normal copy, usually resulting in sufficient protein levels. A person with the deficiency (homozygote) has two copies of the Z allele, which leads to significantly reduced protein levels and higher health risks.
Does having the Z allele mean I will definitely get lung disease?
No, having the Z allele does not guarantee you will develop lung disease. Environmental factors, particularly smoking, significantly influence the risk and severity of lung damage in individuals with this variant.
Should I get tested for the SERPINA1 Z allele?
Testing is typically recommended if you have a family history of alpha-1 antitrypsin deficiency or unexplained lung or liver symptoms. You should discuss the necessity and implications of testing with your doctor.
Is there a cure for alpha-1 antitrypsin deficiency?
There is no cure, but treatments exist to manage the condition. These include augmentation therapy, which involves replacing the missing protein, and lifestyle modifications to protect lung and liver health.
Sources & further reading
Educational information only, last refreshed 10/17/2026. 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.
The classical Pi*Z pathogenic allele in SERPINA1 leading to severe alpha-1 antitrypsin deficiency, lung emphysema, and liver disease.
Known as the S allele (p.Glu288Val), associated with mild alpha-1 antitrypsin deficiency when compounded with Z alleles.