HFE rs1800565: Understanding the S65C Genetic Variant
The rs1800565 variant, commonly known as HFE S65C, is a genetic change in the HFE gene that can influence how the body regulates iron. It is often studied alongside other HFE variants to understand its potential contribution to mild variations in iron accumulation.
What each genotype means
Typical iron regulation
You carry two copies of the standard allele and do not have the HFE S65C alteration. This genotype is associated with baseline transferrin saturation and standard physiological iron handling. It does not confer an elevated genetic risk for HFE-related iron overload.
Carried by approximately 96% to 98% of individuals of European descent and over 99% of most other global ancestries.
Mild iron accumulation tendency
You carry one copy of the S65C missense variant alongside one reference allele. Research shows that single carriers typically do not develop clinical hemochromatosis, although some individuals exhibit mild biochemical elevations in ferritin or transferrin saturation. Significant iron overload is uncommon unless this variant is co-inherited with other major genetic factors, such as the HFE C282Y variant.
Found in about 2% to 4% of individuals of European ancestry, peaking in Northern European populations, and is rare in African, Asian, and Hispanic populations.
Possible mild iron overload risk
You carry two copies of the S65C variant, an uncommon genotype in the general population. Clinical evidence remains limited and mixed, with literature reporting cases ranging from completely normal iron indices to mild or moderate hepatic iron accumulation without severe fibrosis. Because clinical penetrance appears low, this genotype is generally considered a minor risk factor rather than a cause of severe hereditary hemochromatosis.
Extremely rare across all ancestries, occurring in fewer than 1 in 2,500 individuals of Northern European descent and virtually absent in most other populations.
What is the rs1800565 Variant?
The rs1800565 variant, also referred to as S65C (c.193A>T), is a single nucleotide polymorphism (SNP) located within the HFE gene. In this specific genetic change, the amino acid serine is replaced by cysteine at position 65 of the HFE protein sequence. This variant is one of several identified in the HFE gene that researchers monitor when investigating iron metabolism. While it is frequently discussed in the context of hereditary hemochromatosis—a condition characterized by the body absorbing too much iron—the S65C variant is generally considered to have a much milder impact compared to other well-known HFE mutations like C282Y. Because it is a missense variant, it alters the protein's structure, which may affect its function in regulating iron absorption, though the clinical significance of this change remains a subject of ongoing scientific study.
The Role of the HFE Gene
The HFE gene provides instructions for making the HFE protein, which plays a critical role in maintaining healthy iron levels in the body. This protein is found on the surface of cells and interacts with other molecules to regulate the production of hepcidin, a hormone that acts as the master regulator of iron absorption. When the HFE protein functions correctly, it helps ensure that the body absorbs the appropriate amount of iron from the diet. If the HFE protein is altered by certain variants, the signaling pathway that controls iron absorption can be disrupted, potentially leading to increased iron uptake. While the most severe iron overload conditions are typically linked to specific homozygous mutations, variants like S65C are investigated for their potential to contribute to more subtle, mild shifts in iron status, particularly when they occur in combination with other HFE variants.
Research and Clinical Associations
Scientific research into rs1800565 has produced mixed findings regarding its clinical impact. Some studies have suggested that individuals who are compound heterozygotes—meaning they carry the S65C variant on one chromosome and a different HFE variant like C282Y on the other—may show elevated markers of iron, such as increased transferrin saturation or serum ferritin. However, the evidence for S65C acting as a primary cause of iron overload is limited. Many researchers classify it as a variant associated with a mild form of iron metabolism variation rather than a direct cause of severe disease. Because the clinical significance is often debated and findings can vary between different study populations, it is not typically used as a standalone diagnostic marker. Its primary value in research is as a piece of the broader puzzle in understanding how multiple genetic factors interact to influence iron levels.
Population Frequency
The S65C variant is relatively rare compared to other HFE mutations. It is primarily observed in populations of Northern European descent, where the minor allele frequency is typically reported between 1% and 2%. In other global ancestries, the variant is significantly less common or rare. Because of this distribution, most of the existing research on rs1800565 has focused on European cohorts, which limits our understanding of how this variant might manifest in more diverse populations. The frequency data underscores that while the variant is present in the general population, it is not a widespread genetic feature, and its impact is largely confined to specific ancestral groups where it has been historically documented.
Interpreting Your Genetic Information
If you have received information about your rs1800565 genotype, it is important to understand that this variant alone is rarely a cause for medical concern. Genetic associations are statistical observations across large groups of people and do not predict an individual's health outcome. Factors such as diet, alcohol intake, and overall health status play a significant role in iron levels, often outweighing the influence of a single genetic variant. You cannot use this information to diagnose yourself with a medical condition or to determine your iron status. If you are concerned about your iron levels or have a family history of iron-related disorders, the most appropriate step is to consult with a healthcare professional. They can order standard blood tests, such as serum ferritin and transferrin saturation, which provide a direct and accurate measure of your current iron status.
How common is this variant?
The minor allele frequency for rs1800565 is approximately 0.01-0.02 in Northern European populations and is considered rare in other global ancestries.
Frequently asked questions
Does having the S65C variant mean I have hemochromatosis?
No, having the S65C variant does not mean you have hemochromatosis. It is a common genetic variation that is sometimes associated with mild changes in iron levels, but it is not a diagnostic marker for the disease.
Should I change my diet if I have the S65C variant?
There is no standard dietary recommendation for individuals based solely on the S65C variant. If you are concerned about your iron intake, you should discuss your diet and iron levels with a doctor or a registered dietitian.
How can I find out if my iron levels are healthy?
The only way to accurately determine your iron status is through clinical blood tests ordered by a healthcare provider. These tests, such as serum ferritin and transferrin saturation, measure the actual amount of iron in your body.
Is S65C the same as the C282Y mutation?
No, S65C and C282Y are different variants within the HFE gene. C282Y is more strongly associated with hereditary hemochromatosis, while S65C is generally considered to have a much milder or uncertain clinical impact.
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 Ser65Cys missense polymorphism in HFE linked to mild systemic iron regulation changes and downstream impacts on hypogonadotropic reproductive function.
The C282Y missense variant in HFE is the primary genetic cause of hereditary hemochromatosis, leading to iron overload.
Common HFE missense variant H63D associated with hereditary hemochromatosis and mild iron overload risk.
HFE p.His63Asp (H63D) variant contributing to hereditary hemochromatosis risk, especially in compound heterozygosity with C282Y.
Coding variant (p.Val162Met) in the homeostatic iron regulator gene studied alongside classical hemochromatosis variants.
The H63D missense variant in HFE, associated with mild iron overload phenotypes.