HBB rs33930165: Understanding the Codon 39 Nonsense Mutation
The rs33930165 variant in the HBB gene is a well-documented nonsense mutation, specifically known as c.118C>T or p.Gln40Ter (codon 39). It is primarily associated with beta(0)-thalassemia, a condition characterized by the absent production of beta-globin chains in hemoglobin.
What each genotype means
Typical beta-globin genotype
This genotype represents the common, non-mutated sequence at this position in the HBB gene. Individuals with this profile do not carry the specific nonsense mutation associated with beta-thalassemia at this site.
This is the most common genotype observed across all global populations.
Beta-thalassemia carrier status
This genotype indicates you are a carrier of a nonsense mutation (c.118C>T, p.Gln40Ter) in the HBB gene, which is associated with beta-thalassemia. Carriers are typically asymptomatic but may have mild hematological findings; please discuss these results with a genetic counselor or clinician to understand implications for family planning.
This genotype is found at low frequencies in the general population but is enriched in individuals of Mediterranean ancestry.
Beta-thalassemia homozygous state
This genotype indicates the presence of the nonsense mutation on both copies of the HBB gene. This state is associated with beta(0)-thalassemia, a condition that significantly impacts hemoglobin production and requires clinical management by a hematologist.
This genotype is extremely rare in the general population.
What is rs33930165?
The variant rs33930165, often referred to in clinical literature as the codon 39 mutation, is a specific change in the DNA sequence of the HBB gene. Located on chromosome 11, this variant involves a substitution where a cytosine (C) is replaced by a thymine (T) at position 118 of the coding sequence. This change creates a premature stop codon (p.Gln40Ter), which signals the cellular machinery to stop building the beta-globin protein prematurely. Because the resulting protein is truncated and typically unstable, it cannot function correctly. This specific mutation is classified as a nonsense mutation, meaning it effectively halts the production of functional beta-globin chains, leading to a state known as beta(0)-thalassemia when inherited in a homozygous manner.
The Role of the HBB Gene
The HBB gene provides instructions for making the beta-globin subunit of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen from the lungs to the rest of the body. In healthy adults, hemoglobin is composed of two alpha-globin chains and two beta-globin chains. When the HBB gene contains a pathogenic variant like rs33930165, the body's ability to produce sufficient beta-globin is compromised. A lack of beta-globin leads to an imbalance in the hemoglobin structure, which can cause red blood cells to be destroyed prematurely, a process known as hemolysis. This reduction in functional hemoglobin is the hallmark of beta-thalassemia, which can range from mild anemia to severe, transfusion-dependent conditions depending on the specific combination of inherited variants.
Research and Clinical Associations
Research has firmly established rs33930165 as a significant cause of beta-thalassemia, particularly in Mediterranean populations. Studies have shown that this variant is a major contributor to the thalassemia spectrum in regions such as Sicily, where it has been identified in a high percentage of clinical cases. The evidence for its pathogenicity is strong, as it directly disrupts the translation of the beta-globin protein. While the variant is well-characterized, clinical outcomes can vary based on other genetic factors, such as the presence of additional variants in the HBB gene or neighboring genes like HBD. Because this is a recessive condition, individuals who carry only one copy of the variant (heterozygotes) are typically asymptomatic carriers, while those who inherit two copies (homozygotes) or a combination of this variant with another beta-thalassemia variant may experience clinical symptoms.
Population Frequency
The rs33930165 variant is most frequently observed in populations of Mediterranean descent. Data from large-scale genomic databases like gnomAD indicate that the allele frequency is approximately 0.001 in non-Finnish European and Mediterranean populations. While this may seem low, the variant is significantly enriched in specific geographic pockets within Southern Europe, reflecting historical patterns of inheritance in these regions. Because it is a recessive trait, the prevalence of the carrier state is higher than the prevalence of the disease itself. Genetic screening programs in these high-risk populations have been instrumental in identifying carriers and providing information to families regarding the risks of passing the variant to their children.
Managing Genetic Information
Understanding your status regarding rs33930165 is primarily relevant for family planning and carrier screening. If you are identified as a carrier, it does not mean you have the disease, but it does mean there is a possibility of passing the variant to your offspring. If both parents are carriers of beta-thalassemia variants, there is a risk of having a child with a more severe form of the condition. This information should be used in consultation with a genetic counselor or a medical professional who can provide context based on your full genetic profile and family history. It is important to remember that genetic testing results are not a diagnosis of a health condition. Always discuss any concerns about your health or reproductive risks with a qualified clinician who can interpret these findings within the context of your overall medical care.
How common is this variant?
The rs33930165 variant is most common in Mediterranean populations, with an allele frequency of approximately 0.001 in non-Finnish European and Mediterranean groups.
Frequently asked questions
What is beta-thalassemia?
Beta-thalassemia is an inherited blood disorder characterized by reduced or absent production of the beta-globin chain of hemoglobin. This leads to anemia and, in severe cases, requires regular blood transfusions.
Am I at risk if I carry one copy of rs33930165?
Carriers of one copy of this variant are generally asymptomatic. However, if your partner is also a carrier of a beta-thalassemia variant, there is a risk of having a child with a more severe form of the condition.
How is this variant detected?
This variant is typically detected through molecular genetic testing, such as DNA sequencing of the HBB gene. This is often performed as part of carrier screening or diagnostic workups for anemia.
Does this variant affect my medication response?
There is no current evidence linking rs33930165 to specific medication responses. Always consult your clinician or pharmacist regarding any concerns about your medications.
Should I be worried about my health if I have this variant?
If you are a carrier, you are generally healthy, but you should discuss your status with a genetic counselor. If you have two copies, you should be under the care of a hematologist to manage potential anemia.
Sources & further reading
Educational information only, last refreshed 10/15/2026. 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.