IRAK4

interleukin 1 receptor associated kinase 4

Basic information

Region (hg38): 12:43758944-43798307

Links

ENSG00000198001

∙ NCBI:51135 ∙ OMIM:606883 ∙ HGNC:17967 ∙ Uniprot:Q9NWZ3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

immunodeficiency 67 (Supportive), mode of inheritance: AR
immunodeficiency 67 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 67	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious	12637671; 15069404; 16647421; 17893200; 21734245; 26825884

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IRAK4 gene.

Immunodeficiency_67 (243 variants)
Inborn_genetic_diseases (37 variants)
not_provided (19 variants)
IRAK4-related_disorder (4 variants)
Congenital_dyserythropoietic_anemia (2 variants)
Invasive_pneumococcal_disease,_recurrent_isolated (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IRAK4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000016123.4. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	51 clinvar	1 clinvar	54
missense	1 clinvar	1 clinvar	120 clinvar	6 clinvar	1 clinvar	129
nonsense	11 clinvar	1 clinvar				12
start loss						0
frameshift	16 clinvar	1 clinvar				17
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar				5
Total	29	7	122	57	2

Highest pathogenic variant AF is 0.000642182

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IRAK4	protein_coding	protein_coding	ENST00000448290	11	30600

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.80e-9	0.712	125656	0	91	125747	0.000362

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.216	228	237	0.961	0.0000111	3050
Missense in Polyphen		72	87.971	0.81845		1079
Synonymous	0.600	71	77.7	0.913	0.00000352	841
Loss of Function	1.37	16	23.1	0.693	0.00000117	294

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000274	0.000272
Ashkenazi Jewish	0.00	0.00
East Asian	0.000439	0.000435
Finnish	0.000141	0.000139
European (Non-Finnish)	0.000581	0.000580
Middle Eastern	0.000439	0.000435
South Asian	0.000132	0.000131
Other	0.000662	0.000652

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 (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. 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 NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. {ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:17217339, ECO:0000269|PubMed:17337443, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509, ECO:0000269|PubMed:24316379}.;
Disease: DISEASE: Recurrent isolated invasive pneumococcal disease 1 (IPD1) [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. {ECO:0000269|PubMed:16950813}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. {ECO:0000269|PubMed:12637671, ECO:0000269|PubMed:12925671, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:19663824, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Pertussis - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Influenza A - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-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);Regulation of toll-like receptor signaling pathway;IL-1 signaling pathway;AGE-RAGE pathway;Structural Pathway of Interleukin 1 (IL-1);TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;Fibrin Complement Receptor 3 Signaling Pathway;Toll-like Receptor Signaling Pathway;RAGE;TLR NFkB;Toll Like Receptor 7/8 (TLR7/8) Cascade;Signal Transduction;Signaling by Interleukins;TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling;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 5 (TLR5) Cascade;Toll-Like Receptors Cascades;Interleukin-1 signaling;Innate Immune System;Immune System;IL-1 NFkB;IL-1 p38;IL-1 JNK;IL1;TLR p38;IL-7 signaling;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;EPO signaling;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;Toll Like Receptor 4 (TLR4) Cascade;VEGF;Intracellular signaling by second messengers;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;IL1-mediated signaling events;Interleukin-1 family signaling (Consensus)

Recessive Scores

pRec: 0.302

Intolerance Scores

loftool: 0.284
rvis_EVS: -0.25
rvis_percentile_EVS: 35.99

Haploinsufficiency Scores

pHI: 0.0522
hipred: N
hipred_score: 0.322
ghis: 0.569

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: S
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.396

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Irak4
Phenotype: hematopoietic system phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype;

Gene ontology

Biological process: cytokine production;toll-like receptor signaling pathway;neutrophil mediated immunity;MyD88-dependent toll-like receptor signaling pathway;JNK cascade;cytokine-mediated signaling pathway;toll-like receptor 9 signaling pathway;intracellular signal transduction;positive regulation of I-kappaB kinase/NF-kappaB signaling;innate immune response;positive regulation of smooth muscle cell proliferation;positive regulation of NF-kappaB transcription factor activity;interleukin-1-mediated signaling pathway;neutrophil migration
Cellular component: extracellular space;nucleus;cytoplasm;cytosol;plasma membrane;endosome membrane
Molecular function: magnesium ion binding;protein kinase activity;protein serine/threonine kinase activity;interleukin-1 receptor binding;protein binding;ATP binding