What you carry at this position in your DNA and what research says about it.
Iron and Anemia Risk: 10/10 evidence, 53 publications.
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Sample genotype (not yours): A/A
Higher Risk of Low Iron and Anemia
This genotype is associated with lower systemic iron stores and reduced hemoglobin levels. It increases susceptibility to iron deficiency anemia, particularly during periods of high iron demand.
What this genotype means: Lower circulating serum iron and ferritin levels; Increased risk of iron deficiency anemia; Slightly elevated HbA1c levels independent of blood sugar.
Sample genotype (not yours): A/G
Slightly Increased Risk of Low Iron
This genotype is linked to a mild reduction in hemoglobin and iron levels. While generally manageable, it can slightly elevate the risk of iron deficiency under certain physiological conditions.
What this genotype means: Mildly lower hemoglobin and serum iron levels; Slightly higher susceptibility to iron depletion under physical stress; Generally typical red blood cell size and count.
Sample genotype (not yours): G/G
Optimal Iron Absorption and Normal Hemoglobin
This genotype is associated with highly efficient iron absorption and typical hemoglobin levels. It provides natural protection against iron deficiency anemia.
What this genotype means: Efficient dietary iron absorption and mobilization; Typical hemoglobin and red blood cell parameters; Strong natural resistance to iron deficiency anemia.
Gene function and biological role
Gene Function: The TMPRSS6 gene encodes matriptase-2, a transmembrane serine protease that plays a critical role in maintaining systemic iron homeostasis [1]. Matriptase-2 acts as a key negative regulator of hepcidin, a liver-derived hormone that controls systemic iron availability by restricting intestinal iron absorption and iron release from macrophages [1] [2]. By cleaving membrane-bound hemojuvelin, matriptase-2 suppresses hepcidin expression, thereby allowing more dietary iron to enter the bloodstream when body stores are low [2]. Genetic variations that reduce the activity of this gene can lead to inappropriately high hepcidin levels, which restricts iron absorption and can result in iron deficiency anemia [3].
Variant Impact: The rs855791 variant is a common missense mutation in exon 17 of the TMPRSS6 gene that results in a valine-to-alanine amino acid substitution at position 727 (p.Val727Ala) [4]. This change directly alters the catalytic domain of the matriptase-2 protease, modifying its ability to suppress hepcidin transcription [2]. The G allele encodes alanine, which is highly efficient at suppressing hepcidin, leading to optimal iron absorption and higher systemic iron levels [2] [1]. Conversely, the A allele encodes valine, which is less active, resulting in higher hepcidin levels, reduced iron absorption, and lower hemoglobin levels [2] [1].
Key Insight: The A allele of this variant can artificially elevate HbA1c levels by slowing down red blood cell turnover, which can lead to a false impression of higher average blood sugar levels in clinical tests.
Location: TMPRSS6. Chromosome 22 · 22q12.3 · 37.1 Mb
Estimated prevalence by population
Global 15.1%; European 19.0%; African 2.4%; East Asian 30.7%; South Asian 29.1%; Americas 23.4%; Ashkenazi 19.1%; Finnish 12.1%; Middle Eastern 16.6%; Amish 17.5%.
Estimated AA genotype frequency.
Global 42.6%; European 49.2%; African 26.0%; East Asian 49.4%; South Asian 49.7%; Americas 49.9%; Ashkenazi 49.2%; Finnish 45.4%; Middle Eastern 48.3%; Amish 48.7%.
Estimated AG genotype frequency.
Global 42.2%; European 31.8%; African 71.6%; East Asian 19.9%; South Asian 21.2%; Americas 26.6%; Ashkenazi 31.7%; Finnish 42.5%; Middle Eastern 35.1%; Amish 33.8%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Blood Cell & Iron Traits
Iron Levels. Evidence: 10/10. Source: PMID 19820699. Lower Iron.
Hemoglobin Levels. Evidence: 10/10. Source: PMID 19820698. ~0.2 g/dL Lower.
Anemia. Evidence: 8/10. Source: PMID 22323359. Increased Risk.
Diabetes & Glycemic Traits
HbA1c. Evidence: 10/10. Source: PMID 20858683. Slightly Higher.
Showing effects for A/G genotype
Iron Levels. Evidence: 10/10. Source: PMID 19820699. Slightly Lower Iron.
Hemoglobin Levels. Evidence: 10/10. Source: PMID 19820698. ~0.1 g/dL Lower.
Anemia. Evidence: 8/10. Source: PMID 22323359. Slightly Increased.
HbA1c. Evidence: 10/10. Source: PMID 20858683. Typical.
Showing effects for G/G genotype
Iron Levels. Evidence: 10/10. Source: PMID 19820699. Normal Iron.
Hemoglobin Levels. Evidence: 10/10. Source: PMID 19820698. Normal.
Anemia. Evidence: 8/10. Source: PMID 22323359. Typical Risk.
HbA1c. Evidence: 10/10. Source: PMID 20858683. Slightly Lower.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Carrying two copies of the A allele results in a less active form of the matriptase-2 enzyme, which leads to higher circulating levels of the iron-regulatory hormone hepcidin [1]. Elevated hepcidin restricts the absorption of dietary iron in the gut and prevents the release of stored iron into the bloodstream [1] [2]. Consequently, individuals with this genotype have, on average, a 0.2 g/dL reduction in hemoglobin levels and lower serum iron indices [2] [3]. This genetic profile significantly increases the risk of developing iron deficiency anemia, especially in menstruating women, frequent blood donors, or individuals with low dietary iron intake [4]. Interestingly, the slower turnover of red blood cells associated with this genotype can also lead to slightly higher HbA1c readings, which may not accurately reflect actual blood glucose levels [5].
Lower circulating serum iron and ferritin levels; Increased risk of iron deficiency anemia; Slightly elevated HbA1c levels independent of blood sugar.
Sample genotype: AG (Heterozygous)
Having one copy of the A allele and one copy of the G allele results in intermediate matriptase-2 enzyme activity [1]. This leads to a moderate restriction in iron absorption compared to those with the protective G/G genotype [1] [2]. On average, individuals with this genotype experience a modest 0.1 g/dL decrease in hemoglobin levels [3]. While this mild reduction is typically asymptomatic, it can become clinically relevant during times of increased iron demand, such as pregnancy, intense athletic training, or regular blood donation [4]. Monitoring dietary iron intake and routine blood counts can help maintain optimal iron balance and prevent progression to clinical anemia [4].
Mildly lower hemoglobin and serum iron levels; Slightly higher susceptibility to iron depletion under physical stress; Generally typical red blood cell size and count.
Sample genotype: GG (Homozygous)
Carrying two copies of the G allele produces a highly active matriptase-2 enzyme, which effectively suppresses hepcidin expression [1]. This low-hepcidin state allows for optimal absorption of dietary iron through the intestines and efficient mobilization of iron stores throughout the body [1] [2]. Individuals with this genotype typically maintain normal hemoglobin levels, robust serum iron indices, and healthy red blood cell volumes [2] [3]. This genetic makeup is highly protective against iron deficiency anemia, even in populations traditionally at higher risk, such as reproductive-age women [4]. Additionally, because red blood cell lifespan is optimal, HbA1c measurements in these individuals tend to be highly accurate reflections of average blood glucose [5].
Efficient dietary iron absorption and mobilization; Typical hemoglobin and red blood cell parameters; Strong natural resistance to iron deficiency anemia.
Variants with shared genetic architecture
rs4820268 · TMPRSS6 Gene · Chr 22 · Iron and Hemoglobin Levels
rs2413450 · TMPRSS6 Gene · Chr 22 · Red Blood Cell Health
rs11549407 · HBB Gene · Chr 11 · Thalassemia and Anemia Risk
Common variants in TMPRSS6 are associated with iron status and erythrocyte volume.
Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels.
Content updated August 2026.
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