What you carry at this position in your DNA and what research says about it.
Iron Overload Risk: 8/10 evidence, 4 publications.
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Sample genotype (not yours): A/A
Typical Iron Absorption
Normal iron regulation is maintained, and there is no genetic predisposition to hereditary hemochromatosis from this variant. Iron levels in the blood and tissues are expected to remain within the typical range.
What this genotype means: Typical iron absorption; Normal red blood cell size.
Sample genotype (not yours): A/T
Carrier of Mild Hemochromatosis Variant
Inheriting a single copy of the S65C variant slightly increases the potential for iron absorption. While usually harmless on its own, it can contribute to mild iron accumulation under certain conditions.
What this genotype means: Slightly increased iron absorption; Potential for mild iron accumulation if combined with other mutations.
Sample genotype (not yours): T/T
Mildly Elevated Iron Overload Risk
Presence of two copies of the S65C variant can lead to a mild form of hereditary hemochromatosis. Iron levels may gradually accumulate over time, though severe organ damage is rare.
What this genotype means: Mildly increased dietary iron absorption; Elevated red blood cell volume.
Gene function and biological role
Gene Function: The HFE gene encodes a membrane protein that plays a critical role in regulating iron absorption in the body [1]. It works by interacting with other cell-surface proteins to detect iron levels and control the production of hepcidin, the master iron-regulatory hormone [1] [2]. When HFE is functioning normally, it prevents the body from absorbing excess iron from food [2]. Mutations in this gene can disrupt this regulatory pathway, leading to uncontrolled iron uptake and accumulation in vital organs [2] [3]. Over time, this iron overload can cause damage to the liver, heart, and joints [2] [3].
Variant Impact: A missense mutation in the HFE gene results in the substitution of the amino acid serine with cysteine at position 65, commonly known as S65C [2]. This specific structural change alters the HFE protein's ability to properly regulate hepcidin production, leading to a mild increase in intestinal iron absorption [2] [1]. While less severe than the classic C282Y mutation, this variant is recognized as the third most common HFE mutation associated with hereditary hemochromatosis [2] [1]. It typically causes only mild to moderate increases in body iron stores on its own [2]. However, it can contribute to more significant iron accumulation when inherited alongside other HFE mutations [2] [1].
Key Insight: The S65C variant is a very mild genetic contributor to iron overload, and the vast majority of people carrying it never experience severe symptoms.
Location: HFE. Chromosome 6 · 6p22.2 · 26.1 Mb
Estimated prevalence by population
Global 98.0%; European 96.9%; African 99.4%; East Asian 99.9%; South Asian 99.8%; Americas 98.7%; Ashkenazi 99.5%; Finnish 96.3%; Middle Eastern 100.0%; Amish 94.8%.
Estimated AA genotype frequency.
Global 2.0%; European 3.0%; African 0.6%; East Asian 0.1%; South Asian 0.2%; Americas 1.3%; Ashkenazi 0.5%; Finnish 3.7%; Middle Eastern 0.0%; Amish 5.1%.
Estimated AT genotype frequency.
Global < 0.1%; European < 0.1%; African < 0.1%; East Asian < 0.1%; South Asian < 0.1%; Americas < 0.1%; Ashkenazi < 0.1%; Finnish < 0.1%; Middle Eastern 0.0%; Amish 0.1%.
Estimated TT genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Blood Cell & Iron Traits
Iron Overload. Evidence: 3/10. Source: PMID 10194428. Typical Risk.
Red Blood Cell Size. Evidence: 8/10. Source: PMID 32888494. Typical Size.
Red Cell Hemoglobin Content. Evidence: 8/10. Source: PMID 32888494. Typical Levels.
Showing effects for A/T genotype
Iron Overload. Evidence: 3/10. Source: PMID 10194428. Slightly Increased.
Red Blood Cell Size. Evidence: 8/10. Source: PMID 32888494. Slightly Larger.
Red Cell Hemoglobin Content. Evidence: 8/10. Source: PMID 32888494. Slightly Higher.
Showing effects for T/T genotype
Iron Overload. Evidence: 3/10. Source: PMID 10194428. Mildly Elevated.
Red Blood Cell Size. Evidence: 8/10. Source: PMID 32888494. Larger.
Red Cell Hemoglobin Content. Evidence: 8/10. Source: PMID 32888494. Higher.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Normal iron homeostasis is maintained because both copies of the HFE gene produce fully functional proteins [1]. There is no elevated risk of developing hereditary hemochromatosis or abnormal iron accumulation from this specific genetic marker [1] [2]. Red blood cell measurements, including volume and hemoglobin concentration, typically remain within baseline ranges [3]. While other genetic or dietary factors can still influence iron levels, this genotype represents the common, low-risk baseline found in the vast majority of the global population. Routine iron monitoring is generally not required based on this marker alone. Maintaining a balanced diet and healthy lifestyle is sufficient for normal iron regulation. Most individuals with this genotype will never need to worry about genetic iron overload. It serves as a reassuring baseline for overall metabolic health.
Typical iron absorption; Normal red blood cell size.
Sample genotype: AT (Heterozygous)
Inheriting a single copy of the S65C variant typically does not lead to clinical iron overload or hereditary hemochromatosis on its own [1] [2]. The body's iron regulatory mechanisms generally compensate for the slight decrease in hepcidin activity [2]. However, this genotype can become clinically relevant if inherited alongside another HFE mutation, such as C282Y, a state known as compound heterozygosity [1] [2]. Slight increases in red blood cell volume and hemoglobin levels may be observed in genetic carriers [3]. Most carriers live entirely healthy lives without ever developing symptoms of iron overload.
Slightly increased iron absorption; Potential for mild iron accumulation if combined with other mutations.
Sample genotype: TT (Homozygous)
Inheriting two copies of the S65C variant is associated with a mild form of hereditary hemochromatosis [1]. The double mutation moderately impairs the HFE protein's ability to signal for hepcidin, leading to increased dietary iron absorption [1] [2]. While this can elevate body iron stores, the clinical penetrance is low, meaning many individuals with this genotype never develop severe symptoms [1] [2]. Elevated red blood cell volume and hemoglobin concentrations are common physiological features of this genotype [3]. Periodic blood tests to monitor serum ferritin and transferrin saturation are highly recommended to track iron levels. If iron levels become excessively high, simple therapeutic phlebotomy (blood donation) can effectively manage the condition. Limiting alcohol consumption and avoiding raw shellfish are also helpful lifestyle measures to protect liver health. Working with a doctor ensures that any gradual iron accumulation is detected and managed early. This proactive approach prevents any long-term complications associated with iron overload.
Mildly increased dietary iron absorption; Elevated red blood cell volume.
Variants with shared genetic architecture
rs1799945 · HFE Gene · Chr 6 · Iron Overload Risk
rs1800562 · HFE Gene · Chr 6 · Iron Overload Risk
rs79220007 · HFE Gene · Chr 6 · Iron Overload Risk
Meta-analyses of HFE variants in coronary heart disease.
The Polygenic and Monogenic Basis of Blood Traits and Diseases.
Content updated August 2026.
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