HBB rs11549407: Understanding the p.Gln40Ter Variant
The HBB variant rs11549407, also known as p.Gln40Ter or codon 39 nonsense, is a pathogenic genetic change in the hemoglobin subunit beta gene. It is primarily associated with beta-thalassemia, a condition characterized by reduced or absent production of beta-globin chains in hemoglobin.
What each genotype means
Typical beta-globin production
You carry two reference copies of the HBB gene at codon 39. Research indicates normal synthesis of the hemoglobin beta chain from this site, with no increased risk for beta-zero thalassemia associated with this variant. You do not carry the codon 39 nonsense mutation.
Found in more than 99% of the global population, though slightly lower in specific Mediterranean regions where the T allele is enriched.
Beta-thalassemia carrier status
You carry one copy of the pathogenic codon 39 nonsense mutation, traditionally referred to as beta-thalassemia minor or trait. In clinical literature, carriers are typically asymptomatic but often exhibit mild microcytic red blood cells or mild anemia. This genotype also carries reproductive considerations if a partner carries an HBB mutation.
Carried by approximately 1 in 1,500 people globally in gnomAD, but reaches carrier frequencies of 2% to 3% in parts of the Mediterranean (such as Italy and Greece).
Beta-zero thalassemia major
You carry two copies of the codon 39 nonsense mutation, which prevents normal beta-globin chain production from both alleles. In published medical literature, homozygosity for beta-zero mutations leads to beta-thalassemia major, a severe condition typically characterized by profound microcytic anemia from early childhood. Clinical management typically involves specialized hematological care and ongoing monitoring.
Extremely rare worldwide, typically observed at low rates in regions with high carrier frequencies such as Mediterranean populations.
What is the rs11549407 Variant?
The variant rs11549407, commonly referred to in clinical literature as c.118C>T or p.Gln40Ter (and sometimes historically as p.Gln39Ter), is a single nucleotide variant located within the HBB gene. This specific change involves a substitution of cytosine (C) with thymine (T) at position 118 of the coding sequence. This alteration creates a premature termination codon, which signals the cellular machinery to stop building the protein prematurely. Consequently, this leads to the production of a truncated, non-functional protein or triggers nonsense-mediated mRNA decay, a process where the cell degrades the faulty genetic instructions before they can be translated into protein. Because this variant prevents the synthesis of functional beta-globin, it is classified as a pathogenic mutation.
The Role of the HBB Gene
The HBB gene provides instructions for making a protein called beta-globin, which is a vital component of hemoglobin. Hemoglobin is the iron-containing protein in red blood cells that carries oxygen from the lungs to the rest of the body. A functional hemoglobin molecule is typically composed of two alpha-globin subunits and two beta-globin subunits. When the HBB gene contains a pathogenic variant like rs11549407, the body cannot produce enough functional beta-globin. This imbalance leads to the destruction of red blood cells and a shortage of healthy hemoglobin, a condition known as beta-thalassemia. Depending on whether an individual inherits one or two copies of such variants, the clinical presentation can range from mild anemia to severe, transfusion-dependent conditions.
Research and Clinical Associations
Research has firmly established the link between the p.Gln40Ter variant and beta-thalassemia. It has been identified in hundreds of individuals in both homozygous and compound heterozygous states, where it is paired with other HBB variants. The evidence for its pathogenicity is strong, as it directly disrupts the production of the beta-globin chain. Clinical studies have shown that individuals carrying this variant may exhibit symptoms of beta-thalassemia minor (carrier status) if they have one copy, or more severe forms like thalassemia intermedia or major if they inherit two pathogenic variants. It is important to note that clinical outcomes can be influenced by other genetic factors, such as variants in the HBG1 gene or other regulatory regions that might modulate the severity of the condition.
Population Frequency
The rs11549407 variant is found at low frequencies in global populations, consistent with its role as a recessive disease-causing variant. Data from the Genome Aggregation Database (gnomAD) indicates an allele frequency of approximately 0.0003, though this varies by ancestry. It is notably more common in Mediterranean populations, where allele frequencies can reach up to 2-3% in certain regions. Because it is a recessive condition, most carriers are asymptomatic, but the variant remains a significant focus for genetic screening programs in regions where beta-thalassemia is prevalent, such as the Mediterranean, the Middle East, and parts of Africa and Asia.
Managing Genetic Information
Understanding your carrier status for the HBB gene is primarily useful for family planning and reproductive health. If you have received results indicating you carry this variant, it does not mean you have a disease, but it does mean you are a carrier of a recessive trait. If you are concerned about your health or potential risks to offspring, the most appropriate step is to consult with a certified genetic counselor or a medical professional. They can provide context based on your full genetic profile and family history. Never use genetic data to self-diagnose or alter medical treatments. Always discuss any clinical concerns or questions regarding your genetic results with a qualified healthcare provider who can interpret the findings within the context of your overall health.
How common is this variant?
The rs11549407 variant is rare globally, with a gnomAD allele frequency of approximately 0.0003, but it reaches frequencies of up to 2-3% in Mediterranean populations.
Frequently asked questions
What does it mean to be a carrier of HBB p.Gln40Ter?
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.
Can I develop beta-thalassemia from this variant?
Beta-thalassemia is typically an autosomal recessive condition, meaning it usually requires inheriting two pathogenic variants. If you have only one copy, you are a carrier; if you have two, you may have the condition.
Is this variant the same as codon 39 nonsense?
Yes, p.Gln40Ter is often referred to as codon 39 nonsense in older literature. These terms describe the same genetic change that leads to a premature stop in protein production.
Should I be worried if I have this variant?
Finding this variant is common in carrier screening. You should discuss the results with a genetic counselor to understand what it means for your health and family planning.
Sources & further reading
Educational information only, last refreshed 10/12/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant, known as Hb C-Harlem, involves a double mutation in the HBB gene that can lead to sickle-beta-thalassemia-like phenotypes.
A variant in the HBB gene linked to beta-thalassemia carrier status.