HBB rs111033621: Understanding the Codon 39 Beta-Thalassemia Variant
The HBB rs111033621 variant, often referred to as the codon 39 (p.Gln40Ter) mutation, is a well-documented genetic change in the HBB gene. It is primarily associated with beta-thalassemia, a condition characterized by reduced or absent production of beta-globin chains.
What each genotype means
Typical beta-globin profile
This genotype indicates you do not carry the specific p.Gln40Ter (Codon 39) nonsense variant in the HBB gene. Your results suggest you have the common, functional sequence for this specific site, which is associated with normal beta-globin production.
This is the most common genotype globally, found in the vast majority of the human population.
Beta-thalassemia carrier status
You carry one copy of the p.Gln40Ter (Codon 39) variant, which is a known cause of beta-thalassemia. Carriers are typically asymptomatic but may show mild hematological changes; you should discuss these results with a genetic counselor or physician to understand implications for family planning and potential inheritance patterns.
This genotype is found in approximately 1-3% of individuals in specific Mediterranean populations, such as Sardinia, Italy, and Greece.
Beta-thalassemia major risk
This genotype indicates you carry two copies of the p.Gln40Ter (Codon 39) variant, which leads to a loss of function in the HBB gene. This is associated with beta-thalassemia major, a condition requiring ongoing medical management; please consult with a hematologist or medical geneticist for clinical evaluation and care.
This genotype is extremely rare in the general population and is primarily observed in regions with high carrier frequencies where both parents are carriers.
What is rs111033621?
The variant rs111033621 is a single nucleotide polymorphism (SNP) located within the HBB gene, which provides instructions for making the beta-globin protein. In this specific variant, a cytosine (C) is replaced by a thymine (T) at a position often historically described as codon 39. This change creates a premature stop codon, which signals the cell to stop building the protein before it is complete. Because the resulting protein is truncated and typically unstable, it cannot function correctly. This variant is classified as a pathogenic mutation in clinical databases, meaning it is known to cause disease when inherited in specific patterns. It is a classic example of a nonsense mutation, where the genetic code is interrupted early, preventing the synthesis of a functional hemoglobin component.
The Role of the HBB Gene
The HBB gene is essential for the production of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. Hemoglobin is composed of different subunits, including two beta-globin chains. When the HBB gene contains a pathogenic variant like rs111033621, the body's ability to produce these beta-globin chains is severely compromised. This leads to an imbalance in the ratio of alpha-globin to beta-globin chains within red blood cells. The excess alpha-globin chains can damage the red blood cells, leading to their premature destruction, a process known as hemolysis. This imbalance is the hallmark of beta-thalassemia, which can range from mild anemia to severe, transfusion-dependent conditions depending on the specific combination of variants inherited from one's parents.
Research and Clinical Associations
Research has consistently associated rs111033621 with beta-thalassemia. Because it is a 'null' mutation (often denoted as beta-zero), it results in the complete absence of beta-globin production from the affected allele. Clinical evidence, including data from ClinVar, classifies this variant as pathogenic based on numerous submissions linking it to beta-thalassemia major and intermedia. The strength of this association is well-established in the scientific literature, particularly in populations where the variant is prevalent. However, the clinical severity of an individual's condition is not determined by this variant alone; it is influenced by other genetic factors, such as the presence of alpha-globin gene defects or variants in genes that regulate fetal hemoglobin production. Therefore, the presence of this variant indicates carrier status or potential disease risk, but it does not provide a complete picture of an individual's specific clinical prognosis.
Population Frequency
The frequency of the rs111033621 variant is highly dependent on ancestry and geography. It is notably common in Mediterranean populations, with carrier frequencies reaching 1-3% or higher in regions such as Sardinia, Italy, and Greece. In these areas, the variant has been historically maintained due to the selective advantage it may have provided against malaria in carriers. Because of this, it is a standard inclusion in many hemoglobinopathy carrier screening panels for individuals with Mediterranean ancestry. In other global populations, the frequency of this specific variant is significantly lower. Understanding one's carrier status is often a goal of genetic screening programs, which aim to provide individuals with information about the risk of passing the variant to their children, particularly when both parents are carriers.
What This Information Means for You
If you have received information about your status regarding rs111033621, it is important to understand that this is a carrier-status marker. Being a carrier typically means you have one copy of the variant and one normal copy of the HBB gene, which usually does not cause significant health issues. However, if both parents are carriers of a beta-thalassemia variant, there is a risk of having a child with a more severe form of the condition. This information is best used in consultation with a genetic counselor or a medical professional who can interpret the results in the context of your family history and ethnic background. You should never use this information to make medical decisions on your own. Always discuss your genetic results with a qualified clinician to understand the implications for your health and family planning.
How common is this variant?
The rs111033621 variant is a common cause of beta-thalassemia in Mediterranean populations, with carrier frequencies ranging from 1% to 3% in regions like Sardinia and Greece.
Frequently asked questions
Is rs111033621 the same as codon 39?
Yes, rs111033621 is the dbSNP identifier for the mutation historically known as the codon 39 (p.Gln40Ter) variant in the HBB gene. It is a well-characterized nonsense mutation.
What does it mean to be a carrier of this variant?
Being a carrier means you have one copy of the variant and one normal copy of the HBB gene. Carriers are generally healthy but can pass the variant to their children.
Does this variant cause sickle cell disease?
No, this variant is associated with beta-thalassemia, which is a different type of hemoglobin disorder. Sickle cell disease is caused by a different specific variant in the HBB gene.
Should I be worried if I have this variant?
Finding out you are a carrier is useful for family planning. You should discuss the results with a genetic counselor to understand the implications for your health and your children.
Sources & further reading
Educational information only, last refreshed 9/28/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant is a pathogenic mutation in the HBB gene associated with beta-thalassemia.
This variant is a pathogenic mutation in the HBB gene associated with hemoglobinopathies such as sickle cell disease.
This variant (c.20A>T, p.Glu7Val) causes the substitution of valine for glutamic acid in the beta-globin chain, leading to sickle cell trait or disease depending on zygosity.
Pathogenic variant (p.Glu6Val, HbS-Antilles) in HBB associated with sickle cell disease-like pathology.
Pathogenic nonsense mutation (c.118C>T / p.Gln40Ter / codon 39 nonsense) causing beta-zero thalassemia and classic carrier status (beta-thalassemia minor).
This variant, known as Hb C-Harlem, involves a double mutation in the HBB gene that can lead to sickle-beta-thalassemia-like phenotypes.