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 (20 variants)
• IRAK4-related disorder (1 variants)
• not provided (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.

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			2	35	1	38
missense			103	4	2	109
nonsense	10	1				11
start loss						0
frameshift	10	1				11
inframe indel			4			4
splice donor/acceptor (+/-2bp)		2				2
splice region			8	7		15
non coding		1	61	30	42	134
Total	20	5	170	69	45

Highest pathogenic variant AF is 0.000316

Variants in IRAK4

This is a list of pathogenic ClinVar variants found in the IRAK4 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-43758951-C-T		Immunodeficiency 67	Uncertain significance (Jan 13, 2018)
12-43758960-G-A		Immunodeficiency 67	Uncertain significance (Jan 13, 2018)
12-43758961-C-A		Immunodeficiency 67	Uncertain significance (Apr 27, 2017)
12-43758972-G-A		Immunodeficiency 67	Uncertain significance (Jan 12, 2018)
12-43759010-C-G		Immunodeficiency 67	Uncertain significance (Jan 13, 2018)
12-43768107-A-G		Immunodeficiency 67	Uncertain significance (Jan 13, 2018)
12-43768117-C-G		Immunodeficiency 67	Uncertain significance (Feb 06, 2018)
12-43768118-A-C		Immunodeficiency 67	Uncertain significance (Apr 28, 2021)
12-43768123-C-G		Immunodeficiency 67	Likely benign (Oct 07, 2022)
12-43768124-A-G		Immunodeficiency 67	Conflicting classifications of pathogenicity (Jan 09, 2024)
12-43768143-T-G		Immunodeficiency 67	Uncertain significance (Mar 01, 2023)
12-43768145-C-T		Immunodeficiency 67	Conflicting classifications of pathogenicity (Aug 23, 2022)
12-43768146-G-A		Immunodeficiency 67	Uncertain significance (May 10, 2022)
12-43768147-C-T		Immunodeficiency 67	Likely benign (Jan 22, 2021)
12-43768149-G-A		Immunodeficiency 67	Uncertain significance (Mar 01, 2023)
12-43768155-A-G		Immunodeficiency 67	Uncertain significance (Apr 29, 2022)
12-43768169-A-T		Immunodeficiency 67	Uncertain significance (Aug 10, 2022)
12-43768172-A-G		Inborn genetic diseases	Uncertain significance (Dec 13, 2023)
12-43768187-A-G		Immunodeficiency 67	Uncertain significance (Mar 26, 2022)
12-43768188-T-C		Immunodeficiency 67	Uncertain significance (Aug 09, 2022)
12-43768197-A-C		Congenital dyserythropoietic anemia	Uncertain significance (Mar 23, 2023)
12-43768199-G-T		Immunodeficiency 67	Pathogenic (Aug 09, 2017)
12-43768202-G-A		Immunodeficiency 67	Uncertain significance (Sep 03, 2021)
12-43768204-A-T		Immunodeficiency 67	Uncertain significance (Feb 17, 2019)
12-43768210-G-A		Immunodeficiency 67	Likely benign (Nov 27, 2023)

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