The four main types of sickle cell disease are Hemoglobin SS (HbSS), Hemoglobin SC (HbSC), Hemoglobin S beta-zero thalassemia, and Hemoglobin S beta-plus thalassemia. All four result from inheriting two abnormal copies of the gene responsible for making hemoglobin, the protein in red blood cells that carries oxygen. One copy always produces hemoglobin S (the “sickle” variant), while the second copy determines which type of sickle cell disease you have and how severe it is.
How Sickle Cell Types Are Determined
Sickle cell disease is caused by a variation in the HBB gene, which tells your body how to build hemoglobin. You need two altered copies of this gene to have the disease. If you inherit just one copy, you have sickle cell trait and typically don’t experience symptoms. The specific combination of gene variants you inherit from each parent creates your genotype, and that genotype shapes everything from how often you experience pain crises to which organs are most at risk.
Hemoglobin SS (HbSS): Sickle Cell Anemia
HbSS is the most common and most severe form. It occurs when you inherit a hemoglobin S gene from both parents. Because all of your hemoglobin is the sickle type, red blood cells are especially prone to becoming rigid and crescent-shaped, blocking small blood vessels and breaking down faster than normal.
This ongoing destruction of red blood cells, called chronic hemolytic anemia, can cause jaundice, gallstones, and delayed growth in children. The blocked blood vessels lead to episodes of intense pain known as vaso-occlusive crises, which can affect bones, joints, the chest, and abdomen. In children, painful swelling of the hands and feet (dactylitis) is often the very first sign of the disease.
The spleen is particularly vulnerable. Without preventive treatment, most children with HbSS lose spleen function early in life, leaving them at higher risk for serious bacterial infections. Acute chest syndrome, a condition involving fever, chest pain, and difficulty breathing, is one of the leading causes of death in people with HbSS. Over time, repeated damage can affect the brain, kidneys, lungs, and other organs. People with the highest rates of red blood cell breakdown also face elevated risk of high blood pressure in the lungs, leg ulcers, and priapism.
Hemoglobin SC (HbSC)
HbSC disease occurs when you inherit one hemoglobin S gene and one hemoglobin C gene. It is the second most common type of sickle cell disease and is generally milder than HbSS, though it is far from harmless.
People with HbSC have fewer hospitalizations, fewer strokes, and fewer episodes of acute chest syndrome compared to those with HbSS. Pain crises still happen and remain the most common reason for hospital visits in both genotypes. One notable difference: HbSC causes thicker blood (higher viscosity), which creates its own set of problems. Eye complications, specifically a form of retinopathy that can threaten vision, occur more frequently in HbSC than in HbSS. Regular eye exams are especially important for people with this genotype.
Hemoglobin S Beta-Zero Thalassemia
This type results from inheriting one hemoglobin S gene and one beta-thalassemia gene that produces zero normal hemoglobin (beta-zero). Because the thalassemia gene contributes no functional hemoglobin A at all, the disease is clinically almost identical to HbSS. It is classified as a severe form of sickle cell disease.
There is one subtle difference at the cellular level. The thalassemia gene causes red blood cells to be smaller than normal (microcytic), with typical mean cell volumes between 65 and 75 femtoliters, compared to the normal range of roughly 80 to 100. This microcytosis slightly improves how well the smaller cells move through blood vessels and modestly raises overall hemoglobin concentration. However, these cellular advantages don’t translate into fewer pain crises. The sheer proportion of sickle hemoglobin in each cell still drives blockages and organ damage at a rate comparable to HbSS.
Hemoglobin S Beta-Plus Thalassemia
When the inherited beta-thalassemia gene is the “plus” variant rather than “zero,” it still produces some normal hemoglobin A. The amount varies widely, anywhere from less than 5% to as much as 45% of total hemoglobin. That normal hemoglobin A dilutes the sickle hemoglobin inside each red blood cell, interfering with the process that makes cells sickle.
The more normal hemoglobin A present, the milder the disease tends to be. At the low end (very little hemoglobin A), the clinical picture can still be severe and closely resemble HbSS. At higher levels, the disease may be moderate or even mild, with less frequent pain episodes, fewer hospitalizations, and less organ damage. Because of this wide range, S beta-plus thalassemia is the most variable of the four main types. Doctors use lab results showing the percentage of hemoglobin A to help predict how the disease will behave in each person.
Rare Variants Beyond the Main Four
Several less common genotypes also fall under the sickle cell disease umbrella, including HbSD, HbSE, and HbSO. These occur when one hemoglobin S gene pairs with another uncommon hemoglobin variant. HbSE, for example, has historically been considered benign, but accumulating case reports document serious vaso-occlusive symptoms and even fatal complications. Researchers have proposed reclassifying HbSE from mild to moderate sickle cell disease. People with HbSE also tend to develop symptoms later in life, with an average age of first presentation around 21, compared to early childhood for HbSS.
How Sickle Cell Types Are Detected
In the United States, all newborns are screened for sickle cell disease through a simple blood test, a practice recommended since 1987. Early detection allows children to begin preventive antibiotics to protect against the infections that a damaged spleen can no longer fight off. Across Europe, some countries screen every newborn universally, while others use a targeted approach based on family ancestry. India launched a national sickle cell elimination mission that includes newborn screening alongside prevention and treatment programs, with a goal of lowering prevalence by 2047.
The specific genotype is identified during screening, which matters because treatment intensity and monitoring schedules differ by type. A child with HbSS or S beta-zero thalassemia, for instance, will generally need closer follow-up than a child with a milder S beta-plus thalassemia genotype.