IRAK1

interleukin 1 receptor associated kinase 1

Basic information

Region (hg38): X:154010506-154019902

Links

ENSG00000184216 ∙ NCBI:3654 ∙ OMIM:300283 ∙ HGNC:6112 ∙ Uniprot:P51617 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IRAK1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IRAK1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				8	1	9
missense			31	6	7	44
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region				1		1
non coding				2	1	3
Total	0	0	32	16	9

Variants in IRAK1

This is a list of pathogenic ClinVar variants found in the IRAK1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-154011911-C-T		not specified	Uncertain significance (Nov 03, 2023)
X-154012438-C-T		not specified	Benign (Jan 24, 2024)
X-154012535-G-C		not specified	Uncertain significance (Feb 14, 2024)
X-154012537-G-A		not specified	Uncertain significance (Jan 20, 2023)
X-154012606-T-C		not specified	Uncertain significance (Mar 13, 2023)
X-154013049-C-T		IRAK1-related disorder • not specified	Uncertain significance (Mar 15, 2024)
X-154013053-T-C			Likely benign (Sep 01, 2024)
X-154013099-G-A			Benign (Sep 03, 2018)
X-154013118-C-T		IRAK1-related disorder	Likely benign (Feb 01, 2023)
X-154013150-C-A		not specified	Uncertain significance (Jun 06, 2023)
X-154013174-C-T			Benign (Apr 13, 2018)
X-154013175-G-A		not specified	Uncertain significance (May 17, 2023)
X-154013272-T-C			Likely benign (Jul 31, 2018)
X-154013292-A-G		not specified	Uncertain significance (Jan 29, 2024)
X-154013301-C-T		not specified	Uncertain significance (Nov 28, 2023)
X-154013331-C-T		not specified	Likely benign (Jan 23, 2024)
X-154013332-G-A		IRAK1-related disorder	Likely benign (May 08, 2019)
X-154013378-G-A		not specified	Benign (Jan 24, 2024)
X-154013385-C-T		not specified	Uncertain significance (May 30, 2023)
X-154014109-A-G		not specified	Uncertain significance (Dec 03, 2021)
X-154014118-T-C		not specified	Uncertain significance (Dec 06, 2021)
X-154014121-G-C		not specified	Uncertain significance (Dec 06, 2021)
X-154014122-G-C		not specified	Uncertain significance (Dec 06, 2021)
X-154014164-T-A		not specified	Uncertain significance (Oct 06, 2021)
X-154014173-C-T		not specified	Uncertain significance (Dec 19, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IRAK1	protein_coding	protein_coding	ENST00000369980	14	9481

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.988	0.0123	125649	1	1	125651	0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.99	189	283	0.667	0.0000234	4523
Missense in Polyphen		46	107.25	0.42889		1724
Synonymous	0.626	121	130	0.930	0.0000114	1538
Loss of Function	3.96	2	22.1	0.0905	0.00000155	358

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000771	0.0000616
Ashkenazi Jewish	0.000134	0.0000993
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor- signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}.
• Pathway: Pertussis - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Measles - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);JAK-STAT-Ncore;EGF-Ncore;Regulation of toll-like receptor signaling pathway;Apoptosis Modulation and Signaling;IL-1 signaling pathway;EBV LMP1 signaling;Structural Pathway of Interleukin 1 (IL-1);IL1 and megakaryocytes in obesity;Melatonin metabolism and effects;Interleukin-1 Induced Activation of NF-kappa-B;TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;Simplified Depiction of MYD88 Distinct Input-Output Pathway;ApoE and miR-146 in inflammation and atherosclerosis;Fibrin Complement Receptor 3 Signaling Pathway;Toll-like Receptor Signaling Pathway;TLR NFkB;Toll Like Receptor 7/8 (TLR7/8) Cascade;Interleukin-17 signaling;Signal Transduction;Signaling by Interleukins;p75NTR signals via NF-kB;TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling;signal transduction through il1r;nf-kb signaling pathway;toll-like receptor pathway;Cytokine Signaling in Immune system;Toll Like Receptor 9 (TLR9) Cascade;MyD88 cascade initiated on plasma membrane;Toll Like Receptor 10 (TLR10) Cascade;Toll Like Receptor 3 (TLR3) Cascade;Toll Like Receptor 5 (TLR5) Cascade;Toll-Like Receptors Cascades;NOD1/2 Signaling Pathway;Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways;Interleukin-1 signaling;IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation;Innate Immune System;Immune System;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;IL-1 NFkB;IL-1 p38;IL-1 JNK;IL1;TLR p38;IL-7 signaling;TAK1 activates NFkB by phosphorylation and activation of IKKs complex;JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1;activated TAK1 mediates p38 MAPK activation;MAP kinase activation;TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation;MyD88 dependent cascade initiated on endosome;PIP3 activates AKT signaling;JAK STAT pathway and regulation;p75NTR recruits signalling complexes;EPO signaling;NF-kB is activated and signals survival;Death Receptor Signalling;p75 NTR receptor-mediated signalling;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;TLR ECSIT MEKK1 JNK;TLR ECSIT MEKK1 p38;TLR JNK;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;VEGF;Intracellular signaling by second messengers;IRAK1 recruits IKK complex;MyD88:Mal cascade initiated on plasma membrane;Toll Like Receptor TLR1:TLR2 Cascade;Toll Like Receptor TLR6:TLR2 Cascade;Toll Like Receptor 2 (TLR2) Cascade;Endogenous TLR signaling;p75(NTR)-mediated signaling;IL1-mediated signaling events;Interleukin-1 family signaling (Consensus)

Recessive Scores

• pRec: 0.594

Intolerance Scores

• loftool: 0.242
• rvis_EVS: 0.69
• rvis_percentile_EVS: 85.18

Haploinsufficiency Scores

• pHI: 0.176
• hipred: Y
• hipred_score: 0.734
• ghis: 0.421

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.910

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Irak1
• Phenotype: cellular phenotype; muscle phenotype; normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); immune system phenotype

Gene ontology

• Biological process: activation of MAPK activity;regulation of cytokine-mediated signaling pathway;toll-like receptor signaling pathway;MyD88-dependent toll-like receptor signaling pathway;protein phosphorylation;signal transduction;transmembrane receptor protein serine/threonine kinase signaling pathway;activation of NF-kappaB-inducing kinase activity;JNK cascade;aging;viral process;cytokine-mediated signaling pathway;lipopolysaccharide-mediated signaling pathway;negative regulation of NF-kappaB transcription factor activity;positive regulation of type I interferon production;response to lipopolysaccharide;toll-like receptor 2 signaling pathway;toll-like receptor 4 signaling pathway;toll-like receptor 9 signaling pathway;cellular response to heat;intracellular signal transduction;negative regulation of apoptotic process;positive regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of MAP kinase activity;innate immune response;positive regulation of transcription, DNA-templated;protein autophosphorylation;positive regulation of smooth muscle cell proliferation;positive regulation of NF-kappaB transcription factor activity;protein complex oligomerization;type I interferon signaling pathway;nucleotide-binding oligomerization domain containing signaling pathway;interleukin-1-mediated signaling pathway;response to interleukin-1;cellular response to lipopolysaccharide;cellular response to hypoxia;positive regulation of NIK/NF-kappaB signaling;positive regulation of leukocyte adhesion to vascular endothelial cell
• Cellular component: nucleus;cytoplasm;lipid droplet;cytosol;plasma membrane;endosome membrane;interleukin-1 receptor complex
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;NF-kappaB-inducing kinase activity;protein binding;ATP binding;kinase activity;heat shock protein binding;protein homodimerization activity;protein heterodimerization activity