What you carry at this position in your DNA and what research says about it.
Autoimmune Disease Risk: 10/10 evidence, 36 publications.
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Sample genotype (not yours): T/T
Typical Risk of Autoimmune Conditions
A profile with two copies of the T allele is associated with baseline susceptibility to autoimmune disorders. There is no elevated risk for lupus, systemic sclerosis, or primary biliary cholangitis from this variant.
What this genotype means: Typical interferon pathway activity; No elevated risk for lupus; No elevated risk for scleroderma.
Sample genotype (not yours): C/C
Higher Risk of Autoimmune Conditions
Two copies of the C allele are associated with the highest risk of developing autoimmune disorders, including lupus, Sjögren's syndrome, and primary biliary cholangitis. This profile is linked to significantly higher immune system activation.
What this genotype means: Significantly elevated interferon-alpha levels; ~2x higher risk of systemic lupus erythematosus; ~3.4x higher risk of Sjogren's syndrome.
Sample genotype (not yours): T/C
Increased Risk of Autoimmune Conditions
One copy of the C allele is linked to a moderately higher risk of developing autoimmune disorders like lupus and Sjögren's syndrome. This is due to a more active immune response that can trigger inflammation.
What this genotype means: Moderately elevated interferon-alpha levels; ~1.9x higher risk of systemic lupus erythematosus; ~1.7x higher risk of Sjogren's syndrome.
Gene function and biological role
Gene Function: The TNPO3 gene encodes transportin 3, a nuclear import receptor that plays a key role in transporting splicing factors into the cell nucleus [1]. This gene sits adjacent to IRF5, which encodes interferon regulatory factor 5, a transcription factor central to the immune system's response to viral infections and cytokine production [2]. Together, the IRF5-TNPO3 genetic locus is one of the most heavily replicated regions associated with human autoimmune diseases [3]. Variations in this region can alter how immune cells regulate inflammation and self-tolerance [4].
Variant Impact: Located in the downstream region of the TNPO3 gene, rs10488631 closely borders the IRF5 gene. The C allele of this variant acts as a genetic marker for a highly active immune haplotype that increases the expression of interferon regulatory factor 5 [4]. This elevated expression leads to overactivation of the interferon-alpha pathway, a key driver of chronic inflammation [5]. Consequently, this genetic change is strongly linked to a heightened susceptibility to several autoimmune conditions where the body's immune system mistakenly attacks its own tissues [2].
Key Insight: The risk-associated C allele of this variant is linked to a hyperactive interferon pathway, essentially keeping the body's antiviral defense systems on high alert even in the absence of an infection.
Location: TNPO3. Chromosome 7 · 7q32.1 · 129.0 Mb
Estimated prevalence by population
Global 83.0%; European 78.8%; African 95.2%; East Asian 99.6%; South Asian 71.7%; Americas 74.4%; Ashkenazi 78.5%; Finnish 73.1%; Middle Eastern 77.0%; Amish 92.7%.
Estimated TT genotype frequency.
Global 16.0%; European 20.0%; African 4.8%; East Asian 0.4%; South Asian 25.9%; Americas 23.7%; Ashkenazi 20.2%; Finnish 24.8%; Middle Eastern 21.5%; Amish 7.2%.
Estimated TC genotype frequency.
Global 1.0%; European 1.3%; African 0.1%; East Asian < 0.1%; South Asian 2.3%; Americas 1.9%; Ashkenazi 1.3%; Finnish 2.1%; Middle Eastern 1.5%; Amish 0.1%.
Estimated CC genotype frequency.
Showing effects for T/T genotype
Immunity & Inflammation
Autoimmune Diseases
Lupus. Evidence: 10/10. Source: PMID 36750564. Typical Risk.
Systemic Sclerosis. Evidence: 7/10. Source: PMID 20383147. Typical Risk.
Sjogren's Syndrome. Evidence: 3/10. Source: PMID 19092842. Typical Risk.
Rheumatoid Arthritis. Evidence: 5/10. Source: PMID 20453842. Typical Risk.
Organ Systems
Liver Function & Disease
Biliary Cholangitis. Evidence: 7/10. Source: PMID 22936693. Typical Risk.
Showing effects for C/C genotype
Lupus. Evidence: 10/10. Source: PMID 36750564. ~2x Increased Risk.
Systemic Sclerosis. Evidence: 7/10. Source: PMID 20383147. ~1.5x Increased Risk.
Sjogren's Syndrome. Evidence: 3/10. Source: PMID 19092842. ~3.4x Increased Risk.
Rheumatoid Arthritis. Evidence: 5/10. Source: PMID 20453842. ~1.2x Increased Risk.
Biliary Cholangitis. Evidence: 7/10. Source: PMID 22936693. ~3.2x Increased Risk.
Showing effects for T/C genotype
Lupus. Evidence: 10/10. Source: PMID 36750564. ~1.9x Increased Risk.
Sjogren's Syndrome. Evidence: 3/10. Source: PMID 19092842. ~1.7x Increased Risk.
Biliary Cholangitis. Evidence: 7/10. Source: PMID 22936693. ~1.6x Increased Risk.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Carrying two copies of the protective T allele represents the most common genetic profile globally. Individuals with this profile do not experience the elevated interferon-alpha pathway activity associated with the risk variant [1]. Large-scale genome-wide association studies show that this baseline activity correlates with a typical, non-elevated risk for systemic lupus erythematosus [2]. Similarly, clinical data indicate no increased susceptibility to primary biliary cholangitis or Sjögren's syndrome from this locus [3]. While autoimmune diseases are complex and influenced by many environmental and genetic factors, this specific genetic marker does not contribute to an elevated risk. Maintaining a healthy lifestyle and supporting general immune health remain the standard recommendations.
Typical interferon pathway activity; No elevated risk for lupus; No elevated risk for scleroderma.
Sample genotype: CC (Homozygous)
Inheriting two copies of the C risk allele represents the strongest genetic predisposition at this locus for autoimmune diseases. Clinical studies have shown that individuals with this profile have approximately a twofold increased risk of developing systemic lupus erythematosus [1]. The risk is even more pronounced for other conditions, with a 3.2-fold increased risk for primary biliary cholangitis and a 3.4-fold increased risk for Sjögren's syndrome [2]. This genetic variant acts as a marker for a highly active immune haplotype that significantly boosts the expression of interferon regulatory factor 5 [3]. This results in chronically elevated interferon-alpha pathway activity, which can promote systemic inflammation and autoantibody production [4]. Although the genetic risk is elevated, many people with this genotype never develop an autoimmune disease, highlighting the critical role of environmental triggers and lifestyle factors.
Significantly elevated interferon-alpha levels; ~2x higher risk of systemic lupus erythematosus; ~3.4x higher risk of Sjogren's syndrome.
Sample genotype: TC (Heterozygous)
Possessing one copy of the C risk allele is associated with a moderately elevated risk for several autoimmune conditions. Research indicates that carrying this variant is linked to a roughly twofold increase in the risk of developing systemic lupus erythematosus [1]. The C allele also correlates with a 1.6-fold higher risk for primary biliary cholangitis and a 1.7-fold higher risk for Sjögren's syndrome [2]. At the molecular level, this genetic change is associated with increased expression of the nearby IRF5 gene, leading to higher levels of interferon-alpha in the blood [3]. This hyperactive interferon pathway can cause the immune system to more easily target the body's own healthy tissues. While this genotype increases susceptibility, it is not a direct diagnosis, as environmental triggers and other genetic factors play major roles in whether an autoimmune condition actually develops.
Moderately elevated interferon-alpha levels; ~1.9x higher risk of systemic lupus erythematosus; ~1.7x higher risk of Sjogren's syndrome.
Variants with shared genetic architecture
rs2280714 · TNPO3 Gene · Chr 7 · Autoimmune Disease Risk
rs11889341 · STAT4 Gene · Chr 2 · Autoimmune Disease Risk
rs2431697 · PTTG1 Gene · Chr 5 · Lupus and Immune Health
Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.
The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.
Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome.
Content updated August 2026.
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