What you carry at this position in your DNA and what research says about it.
Autoimmune Disease Risk: 8/10 evidence, 26 publications.
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Sample genotype (not yours): T/T
Typical Autoimmune Risk
This genotype represents the common, baseline genetic profile. It is associated with a typical risk of developing autoimmune conditions like rheumatoid arthritis and lupus.
What this genotype means: Typical risk of rheumatoid arthritis and lupus; Standard response to adalimumab therapy.
Sample genotype (not yours): G/G
Elevated Autoimmune Risk
Carrying two copies of the variant allele significantly increases the risk of developing autoimmune conditions like rheumatoid arthritis and lupus. It is also associated with a reduced response to certain TNF-inhibitor medications.
What this genotype means: Elevated risk of rheumatoid arthritis and lupus; Potentially reduced response to adalimumab therapy.
Sample genotype (not yours): T/G
Increased Autoimmune Risk
Carrying one copy of the variant allele is linked to a higher susceptibility to several autoimmune disorders. It may also slightly affect how the body responds to certain biologic therapies.
What this genotype means: Slightly increased risk of rheumatoid arthritis; Increased risk of lupus and Sjögren's complications.
Gene function and biological role
Gene Function: The TNFAIP3 gene encodes the A20 protein, which acts as a critical gatekeeper in the immune system [1]. A20 functions as a negative feedback regulator that restricts inflammatory signaling pathways, particularly the NF-kappaB pathway [1]. Without adequate regulation by this protein, immune cells can become hyperactive and trigger chronic inflammation [2]. Studies in animal models demonstrate that a complete loss of A20 leads to severe, widespread inflammatory disease and premature death [2]. Consequently, maintaining proper TNFAIP3 function is essential for preventing the immune system from attacking the body's own tissues [1].
Variant Impact: A single nucleotide change from thymine to guanine results in the replacement of the amino acid phenylalanine with cysteine at position 127 of the A20 protein. This structural change, known as p.Phe127Cys, is thought to reduce the protein's ability to efficiently suppress inflammatory signals [2]. Because the altered protein is less effective at dampening immune responses, the body remains in a more active inflammatory state [2]. This persistent activation increases susceptibility to several chronic autoimmune conditions [3]. The variant is relatively common in populations of African ancestry but occurs at lower frequencies in European and Asian groups.
Key Insight: Although this variant increases the risk of several common autoimmune diseases, ClinVar classifies it as benign for a rare autoinflammatory syndrome, showing how genetic effects can be highly specific.
Location: TNFAIP3. Chromosome 6 · 6q23.3 · 137.9 Mb
Estimated prevalence by population
Global 78.4%; European 93.8%; African 40.6%; East Asian 91.6%; South Asian 93.9%; Americas 85.9%; Ashkenazi 91.4%; Finnish 96.7%; Middle Eastern 88.8%; Amish 100.0%.
Estimated TT genotype frequency.
Global 17.8%; European 6.1%; African 46.2%; East Asian 8.2%; South Asian 6.0%; Americas 13.6%; Ashkenazi 8.4%; Finnish 3.3%; Middle Eastern 10.9%; Amish 0.0%.
Estimated TG genotype frequency.
Global 3.7%; European 0.1%; African 13.2%; East Asian 0.2%; South Asian 0.1%; Americas 0.5%; Ashkenazi 0.2%; Finnish < 0.1%; Middle Eastern 0.3%; Amish 0.0%.
Estimated GG genotype frequency.
Showing effects for T/T genotype
Immunity & Inflammation
Autoimmune Diseases
Rheumatoid Arthritis. Evidence: 5/10. Source: PMID 22402800. Typical Risk.
Lupus. Evidence: 8/10. Source: PMID 19838193. Typical Risk.
Systemic Sclerosis. Evidence: 4/10. Source: PMID 28314753. Typical Risk.
Cancer & Oncology
Blood Cancers
Sjogren's Lymphoma Risk. Evidence: 3/10. Source: PMID 26338037. Typical Risk.
Pharmacogenomics
Immunosuppressant & Biologic Response
Adalimumab Response. Evidence: 5/10. Source: PMID 28639493. Stronger Response.
Showing effects for G/G genotype
Rheumatoid Arthritis. Evidence: 5/10. Source: PMID 22402800. ~1.4x Increased Risk.
Lupus. Evidence: 8/10. Source: PMID 19838193. Increased Risk.
Systemic Sclerosis. Evidence: 4/10. Source: PMID 28314753. Increased Risk.
Sjogren's Lymphoma Risk. Evidence: 3/10. Source: PMID 26338037. ~2.5x Increased Risk.
Adalimumab Response. Evidence: 5/10. Source: PMID 28639493. Poorer Response.
Showing effects for T/G genotype
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
Two copies of the common thymine allele ensure the production of a fully functional A20 protein. This standard protein structure efficiently regulates the NF-kappaB pathway, preventing unnecessary or prolonged immune activation [1]. Consequently, this genetic profile is associated with a typical baseline risk for developing autoimmune conditions such as rheumatoid arthritis [2]. It also correlates with a standard risk for systemic lupus erythematosus and systemic sclerosis [3]. Furthermore, clinical data suggest that this genotype is linked to a more favorable response to certain biologic therapies, such as the TNF-inhibitor adalimumab [4]. A typical genetic makeup means the body's natural anti-inflammatory brakes function as expected. No additional genetic risk for Sjögren's syndrome-associated lymphoma is present with this profile [5].
Typical risk of rheumatoid arthritis and lupus; Standard response to adalimumab therapy.
Sample genotype: GG (Homozygous)
Two copies of the guanine variant result in all produced A20 proteins containing the cysteine substitution. This complete alteration significantly reduces the protein's capacity to inhibit the NF-kappaB pathway, allowing inflammatory signals to persist [1]. As a result, this genotype is strongly associated with an increased susceptibility to multiple autoimmune disorders [2]. Research indicates a 1.4-fold higher risk of developing rheumatoid arthritis compared to the typical genotype [3]. The risk for systemic lupus erythematosus is also elevated with this profile [4]. Furthermore, in patients diagnosed with Sjögren's syndrome, this genetic makeup is linked to a more than twofold increase in the risk of non-Hodgkin lymphoma [5]. Response to certain biologic treatments, such as the TNF-inhibitor adalimumab, may also be less effective compared to those carrying the thymine allele [6].
Elevated risk of rheumatoid arthritis and lupus; Potentially reduced response to adalimumab therapy.
Sample genotype: TG (Heterozygous)
One copy of the guanine variant introduces an altered version of the A20 protein into the immune system. This structural change slightly impairs the protein's ability to shut down inflammatory signals, leading to a mild increase in baseline immune activity [1]. Clinical studies have linked this heterozygous profile to a 1.4-fold increased risk of developing rheumatoid arthritis [2]. It is also associated with a higher susceptibility to systemic lupus erythematosus [3]. In patients with Sjögren's syndrome, this variant more than doubles the risk of developing associated non-Hodgkin lymphoma [4]. Despite these elevated risks, the presence of one normal thymine allele still provides substantial anti-inflammatory control. Additionally, individuals with this genotype generally maintain a favorable response to TNF-inhibitor medications like adalimumab [5].
Slightly increased risk of rheumatoid arthritis; Increased risk of lupus and Sjögren's complications.
Variants with shared genetic architecture
rs582757 · TNFAIP3 Gene · Chr 6 · Psoriasis Risk
rs610604 · TNFAIP3 Gene · Chr 6 · Autoimmune Disease Risk
rs6920220 · TNFAIP3 Gene · Chr 6 · Rheumatoid Arthritis Risk
Associations between TNFAIP3 gene polymorphisms and systemic lupus erythematosus: a meta-analysis.
Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis: a meta-analysis.
Germline variation of TNFAIP3 in primary Sjögren's syndrome-associated lymphoma.
Content updated August 2026.
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