Autoinflammatory syndrome: genes and variants

Genes linked to Autoinflammatory syndrome

• NLRP3: NACHT, LRR and PYD domains-containing protein 3

  It assembles a widely used inflammasome in response to diverse danger signals, driving caspase-1 activation and release of IL-1beta and IL-18. Gain-of-function variants cause cryopyrin-associated periodic syndromes, while excessive activation contributes to common inflammatory diseases.

  7 disease-causing and 2 uncertain variants in NLRP3 are linked to Autoinflammatory syndrome.

• TNFRSF1A: Tumor necrosis factor receptor superfamily member 1A

  It mediates many inflammatory and cell-death responses to TNF through NF-kappaB, MAPK, and death-domain signaling. Dominant pathogenic variants that alter receptor handling cause TNF receptor-associated periodic syndrome, an inherited autoinflammatory disease.

  3 disease-causing and 19 uncertain variants in TNFRSF1A are linked to Autoinflammatory syndrome.

• UNC13D: Protein unc-13 homolog D

  It primes cytotoxic granules for membrane fusion in natural-killer cells and cytotoxic T cells, enabling release of perforin and granzymes. Biallelic loss-of-function variants cause familial hemophagocytic lymphohistiocytosis type 3 with uncontrolled immune activation.

  2 disease-causing and 30 uncertain variants in UNC13D are linked to Autoinflammatory syndrome.

• SH2D1A: SH2 domain-containing protein 1A

  It coordinates signaling through SLAM-family immune receptors and is essential for normal T-cell and natural-killer-cell responses to Epstein-Barr virus. Loss-of-function variants cause X-linked lymphoproliferative disease type 1, with fulminant EBV-associated immune dysregulation.

  1 disease-causing and 1 uncertain variants in SH2D1A are linked to Autoinflammatory syndrome.

• MEFV: Pyrin

  Its pyrin inflammasome senses disruptions of cytoskeletal regulation and can activate IL-1beta-dependent inflammation. Pathogenic variants cause familial Mediterranean fever, with recurrent attacks of fever and serosal or joint inflammation.

  0 disease-causing and 31 uncertain variants in MEFV are linked to Autoinflammatory syndrome.

• LYST: Lysosomal-trafficking regulator

  It controls size, trafficking, and exocytosis of lysosome-related organelles in immune cells, melanocytes, and other tissues. Biallelic loss-of-function variants cause Chediak-Higashi syndrome with partial albinism, recurrent infection, bleeding, and risk of hemophagocytic lymphohistiocytosis.

  0 disease-causing and 36 uncertain variants in LYST are linked to Autoinflammatory syndrome.

• PSTPIP1: Proline-serine-threonine phosphatase-interacting protein 1

  It organizes cytoskeletal and inflammasome-associated protein interactions in myeloid cells and can influence pyrin-dependent inflammatory signaling. Gain-of-function variants cause PAPA syndrome and related PSTPIP1-associated autoinflammatory diseases with sterile arthritis and inflammatory skin lesions.

  0 disease-causing and 29 uncertain variants in PSTPIP1 are linked to Autoinflammatory syndrome.

• NOD2: Nucleotide-binding oligomerization domain-containing protein 2

  It detects bacterial muramyl dipeptide in the cytosol and activates antimicrobial and inflammatory responses. Common loss-of-function variants strongly increase Crohn-disease susceptibility, whereas distinct gain-of-function variants cause Blau syndrome.

  0 disease-causing and 23 uncertain variants in NOD2 are linked to Autoinflammatory syndrome.

• IL1RN: Interleukin-1 receptor antagonist protein

  It competitively blocks IL-1 receptor activation without triggering inflammatory signaling, providing an endogenous brake on IL-1-mediated inflammation. Biallelic loss-of-function variants cause deficiency of the IL-1 receptor antagonist, a severe neonatal autoinflammatory disease with skin and bone inflammation.

  0 disease-causing and 4 uncertain variants in IL1RN are linked to Autoinflammatory syndrome.

• XIAP: E3 ubiquitin-protein ligase XIAP

  It directly restrains caspases and also participates in innate immune signaling, thereby controlling apoptosis and inflammatory responses. Loss-of-function variants cause X-linked lymphoproliferative syndrome type 2, with hemophagocytic lymphohistiocytosis, inflammatory bowel disease, and recurrent hyperinflammation.

  0 disease-causing and 2 uncertain variants in XIAP are linked to Autoinflammatory syndrome.

Weakly linked (only a few uncertain records): HMGCR.

Where Autoinflammatory syndrome variants cluster

• NLRP3 NACHT (positions 220–536): 6 of 7 disease-causing changes, 2.8× more than its size predicts.

Known disease-causing variants in Autoinflammatory syndrome

Which prediction tools work for Autoinflammatory syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 98 out of 100
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 80 out of 100

Same protein, different disease

• Cryopyrin associated periodic syndrome is also caused by NLRP3 variants; they fall partly in the same places as the Autoinflammatory syndrome variants (15 disease-causing).
• Chronic infantile neurological, cutaneous and articular syndrome is also caused by NLRP3 variants; they fall mostly in different places as the Autoinflammatory syndrome variants (5 disease-causing).
• Familial amyloid nephropathy with urticaria AND deafness is also caused by NLRP3 variants; they fall mostly in different places as the Autoinflammatory syndrome variants (4 disease-causing).
• TNF receptor-associated periodic fever syndrome (TRAPS) is also caused by TNFRSF1A variants; they fall mostly in different places as the Autoinflammatory syndrome variants (21 disease-causing).
• Familial hemophagocytic lymphohistiocytosis is also caused by UNC13D variants; they fall mostly in different places as the Autoinflammatory syndrome variants (7 disease-causing).
• X-linked lymphoproliferative disease due to SH2D1A deficiency is also caused by SH2D1A variants; they fall mostly in different places as the Autoinflammatory syndrome variants (7 disease-causing).

Diseases related to Autoinflammatory syndrome

• Behcet disease, also linked to MEFV and TNFRSF1A
• Autosomal dominant nonsyndromic hearing loss, also linked to NLRP3
• TNF receptor-associated periodic fever syndrome (TRAPS), also linked to TNFRSF1A
• Cryopyrin associated periodic syndrome, also linked to NLRP3
• Blau syndrome, also linked to NOD2
• Regional enteritis, also linked to NOD2
• Familial hemophagocytic lymphohistiocytosis, also linked to UNC13D
• Inflammatory bowel disease, also linked to NOD2
• X-linked lymphoproliferative disease due to SH2D1A deficiency, also linked to SH2D1A
• Familial Mediterranean fever, also linked to MEFV
• Chédiak-Higashi syndrome, also linked to LYST
• Chronic infantile neurological, cutaneous and articular syndrome, also linked to NLRP3

Frequently asked questions

Which genes are linked to Autoinflammatory syndrome?

In CATVariant, Autoinflammatory syndrome is linked to 10 analyzed proteins: NLRP3 (NACHT, LRR and PYD domains-containing protein 3), TNFRSF1A (Tumor necrosis factor receptor superfamily member 1A), UNC13D (Protein unc-13 homolog D), SH2D1A (SH2 domain-containing protein 1A), MEFV (Pyrin), LYST (Lysosomal-trafficking regulator) and 4 more.

How many genetic variants are linked to Autoinflammatory syndrome?

254 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 178 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autoinflammatory syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Autoinflammatory syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 8 disease-causing and 17 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center