IRAK1

protein-coding

interleukin 1 receptor associated kinase 1

Gene summary

This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001569.4

Inheritance

ClinVar variants

U:143B:41

Top phenotype

systemic lupus erythematosus

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chrX:154,010,506-154,019,902

External References & Databases

Ensembl (ENSG00000184216)

Transcript & Mutation Effects

hg38 • Region Span ~9.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

immunodeficiency diseaseLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0021094

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRAK1 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 98

not providedTotal: 21

IRAK1-related disorderTotal: 19

Apneic episodes in infancyTotal: 1

Unilateral ptosisTotal: 1

Cleft palateTotal: 1

Inguinal herniaTotal: 1

High palateTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001569.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			13 clinvar	23 clinvar		36
missense			108 clinvar	15 clinvar	3 clinvar	126
nonsense			9 clinvar			9
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	0	0	143	38	3	184

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001569.4	RefSeq	NP_001560.2	14	MANE Select
ENST00000369980.8	Ensembl	ENSP00000358997.3	14	MANE Select
NM_001025242.2	RefSeq	NP_001020413.1	14	Standard
NM_001025243.2	RefSeq	NP_001020414.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
NF-kappaB-inducing kinase activity
protein binding
ATP binding

Cellular Component

nucleus
cytoplasm
lipid droplet
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369980
Coding exons: 14
Length: 9481
Individuals with no LoFs: 125649
Homozygous LoFs: 1
Heterozygous LoFs: 1
Defined: 125651
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.99	189	283	0.667	0.0000234	4523
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000077	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.594

Intolerance Scores

LoFtool: 0.242
RVIS EVS: 0.69
RVIS percentile EVS: 85.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.910

Gene Damage Prediction

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