IRAK1
Chr Xinterleukin 1 receptor associated kinase 1
Also known as: IRAK, pelle
The protein functions as a serine/threonine kinase that initiates innate immune responses by mediating Toll-like receptor and IL-1 receptor signaling pathways, leading to NF-kappa B activation and interferon regulatory factor 7 phosphorylation. Mutations cause X-linked immunodeficiency, which typically presents with recurrent infections and increased susceptibility to pyogenic bacteria. This gene is highly constrained against loss-of-function variants and follows X-linked inheritance.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
300 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 101 | 0 | 101 |
Likely Pathogenic | 0 | 0 | 4 | 0 | 4 |
VUS | 1 | 63 | 11 | 0 | 75 |
Likely Benign | 0 | 6 | 2 | 12 | 20 |
Benign | 0 | 8 | 1 | 2 | 11 |
Conflicting | — | 2 | |||
| Total | 1 | 77 | 119 | 14 | 213 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
IRAK1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Pacritinib For Bone Marrow Fibrosis In Patients With Myelofibrosis Who Have Thrombocytopenia
RECRUITINGPacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome
RECRUITINGExternal Resources
Links to major genomics databases and tools