Immunodeficiency 67

Summary

Immunodeficiency 67 (MONDO:0011888) is a disease caused by IRAK4 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IRAK4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 324
• Phenotypes (HPO): 7
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		49	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0001875	Decreased total neutrophil count	Very frequent (80-99%)
HP:0002718	Recurrent bacterial infections	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0005366	Recurrent streptococcus pneumoniae infections	Very frequent (80-99%)
HP:0007499	Recurrent staphylococcal infections	Very frequent (80-99%)
HP:0005406	Recurrent bacterial skin infections	Frequent (30-79%)
HP:0001945	Fever	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 67
Mondo ID	MONDO:0011888
MeSH	C563662, C564352
OMIM	607676
Orphanet	70592
UMLS	C1843256
MedGen	375137
GARD	0010311
Is cancer (heuristic)	no

Also known as: immunodeficiency 67 · immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency · Interleukin receptor-associated kinase deficiency · invasive pneumococcal disease, recurrent isolated, 1 · invasive pneumococcal disease, recurrent isolated, type 1 · IPD1 · IRAK-4 deficiency · IRAK4 deficiency · IRAK4D

Data availability: 324 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 67

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

324 retrieved; paginated sample, class counts are floors:

150 uncertain significance, 104 likely benign, 29 pathogenic, 25 benign, 7 conflicting classifications of pathogenicity, 5 likely pathogenic, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012217	NM_016123.4(IRAK4):c.364C>T (p.Gln122Ter)	IRAK4	Pathogenic	criteria provided, multiple submitters, no conflicts
1012218	NC_000012.12:g.43775405_43788500del	IRAK4	Pathogenic	criteria provided, single submitter
1069901	NM_016123.4(IRAK4):c.540del (p.Phe180fs)	IRAK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427828	NM_016123.4(IRAK4):c.288_304del (p.Ala97fs)	IRAK4	Pathogenic	criteria provided, single submitter
1456107	NM_016123.4(IRAK4):c.1135G>T (p.Glu379Ter)	IRAK4	Pathogenic	criteria provided, single submitter
1457405	NM_016123.4(IRAK4):c.1290C>G (p.Tyr430Ter)	IRAK4	Pathogenic	criteria provided, single submitter
1459926	NC_000012.11:g.(?44176090)(44176313_?)del	IRAK4	Pathogenic	criteria provided, single submitter
1803983	NM_016123.4(IRAK4):c.333del (p.Leu112fs)	IRAK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2053205	NM_016123.4(IRAK4):c.652delA (p.Met218fs)	IRAK4	Pathogenic	criteria provided, single submitter
2137317	NM_016123.4(IRAK4):c.1146del (p.Gly383fs)	IRAK4	Pathogenic	criteria provided, single submitter
2137318	NM_016123.4(IRAK4):c.1204G>T (p.Glu402Ter)	IRAK4	Pathogenic	criteria provided, single submitter
2790034	NM_016123.4(IRAK4):c.181C>T (p.Gln61Ter)	IRAK4	Pathogenic	criteria provided, single submitter
2803498	NM_016123.4(IRAK4):c.274_281dup (p.Phe94fs)	IRAK4	Pathogenic	criteria provided, single submitter
2818504	NM_016123.4(IRAK4):c.629_630del (p.Val210fs)	IRAK4	Pathogenic	criteria provided, single submitter
2837459	NM_016123.4(IRAK4):c.1039A>T (p.Arg347Ter)	IRAK4	Pathogenic	criteria provided, single submitter
3002605	NM_016123.4(IRAK4):c.143dup (p.Tyr48Ter)	IRAK4	Pathogenic	criteria provided, single submitter
3244312	NC_000012.11:g.(?44161915)(44180518_?)del	IRAK4	Pathogenic	criteria provided, single submitter
3648245	NM_016123.4(IRAK4):c.554_556delinsGGGGTACATATTAGCATTTTGTACCATTATTATTGGTGCTAAAGTTTGATCACTTGGTGAAGGAAGTGTACTTCAGATTTCCTCATTAAAAATGTACCCTTCTCTTTCATACTTCACAAGTAATTTGTGTACAATACTTTTTCTCTATCTATTGAGGGGGTCTTGCTCTGTCACTCAGGCTGGAGTGCAGTGGCATGATCATGGCTCACTGCAGCCTTGACTTCCTGGGCTCAGGTGATCCTCCCACCTCAACCTCCCAAGTAGCTGGGACTACAGGCGTGCACTACCACACCCAGCTAATTTTTTGTAGTGATGGGGTTTTAC (p.Ile185_Ser186delinsArgGlyThrTyrTer)	IRAK4	Pathogenic	criteria provided, single submitter
3662862	NM_016123.4(IRAK4):c.797_798del (p.Pro266fs)	IRAK4	Pathogenic	criteria provided, single submitter
3838	NM_016123.4(IRAK4):c.821del (p.Leu274fs)	IRAK4	Pathogenic	no assertion criteria provided
3839	NM_016123.4(IRAK4):c.877C>T (p.Gln293Ter)	IRAK4	Pathogenic	criteria provided, multiple submitters, no conflicts
3840	NM_016123.4(IRAK4):c.623_624del (p.Thr208fs)	IRAK4	Pathogenic	no assertion criteria provided
3841	NM_016123.4(IRAK4):c.1189-1G>T	IRAK4	Pathogenic	no assertion criteria provided
464933	NM_016123.4(IRAK4):c.224del (p.Gly75fs)	IRAK4	Pathogenic	criteria provided, single submitter
533523	NM_016123.4(IRAK4):c.88G>T (p.Glu30Ter)	IRAK4	Pathogenic	criteria provided, single submitter
567326	NM_016123.4(IRAK4):c.547C>T (p.Arg183Ter)	IRAK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
846951	NM_016123.4(IRAK4):c.869_885del (p.Lys290fs)	IRAK4	Pathogenic	criteria provided, single submitter
853817	NM_016123.4(IRAK4):c.781del (p.Val261fs)	IRAK4	Pathogenic	criteria provided, single submitter
858438	NM_016123.4(IRAK4):c.518T>A (p.Leu173Ter)	IRAK4	Pathogenic	criteria provided, single submitter
870469	NM_016123.4(IRAK4):c.1049del (p.Gly350fs)	IRAK4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IRAK4	Strong	Autosomal recessive	immunodeficiency 67	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRAK4	Orphanet:70592	Transient predisposition to invasive pyogenic bacterial infection

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IRAK4	HGNC:17967	ENSG00000198001	Q9NWZ3	Interleukin-1 receptor-associated kinase 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRAK4	Interleukin-1 receptor-associated kinase 4	Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IRAK4	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRAK4	224	ubiquitous	yes	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRAK4	2,977

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IRAK4	Q9NWZ3	96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IRAK4 deficiency (TLR5)	1	2855.0×	0.009	IRAK4
Diseases of Immune System	1	878.5×	0.009	IRAK4
Diseases associated with the TLR signaling cascade	1	878.5×	0.009	IRAK4
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling	1	878.5×	0.009	IRAK4
IRAK4 deficiency (TLR2/4)	1	571.0×	0.011	IRAK4
Negative regulation of the PI3K/AKT network	1	278.5×	0.011	IRAK4
Interleukin-1 family signaling	1	271.9×	0.011	IRAK4
Toll Like Receptor 10 (TLR10) Cascade	1	215.5×	0.011	IRAK4
Toll Like Receptor 5 (TLR5) Cascade	1	215.5×	0.011	IRAK4
MyD88 cascade initiated on plasma membrane	1	203.9×	0.011	IRAK4
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	190.3×	0.011	IRAK4
MyD88 dependent cascade initiated on endosome	1	190.3×	0.011	IRAK4
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	184.2×	0.011	IRAK4
Toll Like Receptor 9 (TLR9) Cascade	1	175.7×	0.011	IRAK4
Toll Like Receptor TLR6:TLR2 Cascade	1	175.7×	0.011	IRAK4
Toll Like Receptor 2 (TLR2) Cascade	1	173.0×	0.011	IRAK4
Toll Like Receptor TLR1:TLR2 Cascade	1	167.9×	0.011	IRAK4
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	152.3×	0.011	IRAK4
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.012	IRAK4
Toll-like Receptor Cascades	1	124.1×	0.012	IRAK4
Interleukin-1 signaling	1	124.1×	0.012	IRAK4
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.014	IRAK4
Intracellular signaling by second messengers	1	91.4×	0.014	IRAK4
PIP3 activates AKT signaling	1	66.8×	0.019	IRAK4
Signaling by Interleukins	1	64.2×	0.019	IRAK4
Cytokine Signaling in Immune system	1	40.8×	0.028	IRAK4
Innate Immune System	1	25.5×	0.044	IRAK4
Disease	1	13.1×	0.080	IRAK4
Immune System	1	13.0×	0.080	IRAK4
Signal Transduction	1	10.2×	0.098	IRAK4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Toll signaling pathway	1	2407.4×	0.002	IRAK4
interleukin-33-mediated signaling pathway	1	2106.5×	0.002	IRAK4
toll-like receptor 9 signaling pathway	1	1872.4×	0.002	IRAK4
neutrophil mediated immunity	1	1404.3×	0.002	IRAK4
neutrophil migration	1	1404.3×	0.002	IRAK4
MyD88-dependent toll-like receptor signaling pathway	1	936.2×	0.003	IRAK4
interleukin-1-mediated signaling pathway	1	802.5×	0.003	IRAK4
toll-like receptor signaling pathway	1	601.9×	0.003	IRAK4
lipopolysaccharide-mediated signaling pathway	1	526.6×	0.003	IRAK4
toll-like receptor 4 signaling pathway	1	526.6×	0.003	IRAK4
positive regulation of smooth muscle cell proliferation	1	330.4×	0.004	IRAK4
JNK cascade	1	271.8×	0.005	IRAK4
cytokine-mediated signaling pathway	1	130.6×	0.009	IRAK4
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	IRAK4
intracellular signal transduction	1	38.1×	0.028	IRAK4
innate immune response	1	33.6×	0.030	IRAK4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
IRAK4	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IRAK4	43	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	IRAK4
FEDRATINIB	4	IRAK4
VANDETANIB	4	IRAK4
BOSUTINIB	4	IRAK4
GILTERITINIB	4	IRAK4
NINTEDANIB	4	IRAK4
SUNITINIB	4	IRAK4
DASATINIB	4	IRAK4
QUIZARTINIB	4	IRAK4
CRIZOTINIB	4	IRAK4
GEFITINIB	4	IRAK4
CRENOLANIB	3	IRAK4
LINIFANIB	3	IRAK4
CANERTINIB	3	IRAK4
TESEVATINIB	3	IRAK4
ALVOCIDIB	3	IRAK4
DOVITINIB	3	IRAK4
LESTAURTINIB	3	IRAK4
SU-014813	2	IRAK4
REBASTINIB	2	IRAK4
MK-2461	2	IRAK4
CENISERTIB	2	IRAK4
ILORASERTIB	2	IRAK4
LAUROGUADINE	2	IRAK4
SCH-900776	2	IRAK4
ZIMLOVISERTIB	2	IRAK4
BMS-919373	2	IRAK4
R-406	2	IRAK4
EMAVUSERTIB	2	IRAK4
BI-2536	2	IRAK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
IRAK4	799	Binding:795, Functional:3, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
IRAK4	799

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	IRAK4
FEDRATINIB	4	IRAK4
VANDETANIB	4	IRAK4
BOSUTINIB	4	IRAK4
GILTERITINIB	4	IRAK4
NINTEDANIB	4	IRAK4
SUNITINIB	4	IRAK4
DASATINIB	4	IRAK4
QUIZARTINIB	4	IRAK4
CRIZOTINIB	4	IRAK4
GEFITINIB	4	IRAK4
CRENOLANIB	3	IRAK4
LINIFANIB	3	IRAK4
CANERTINIB	3	IRAK4
TESEVATINIB	3	IRAK4
ALVOCIDIB	3	IRAK4
DOVITINIB	3	IRAK4
LESTAURTINIB	3	IRAK4
SU-014813	2	IRAK4
REBASTINIB	2	IRAK4
MK-2461	2	IRAK4
CENISERTIB	2	IRAK4
ILORASERTIB	2	IRAK4
LAUROGUADINE	2	IRAK4
SCH-900776	2	IRAK4
ZIMLOVISERTIB	2	IRAK4
BMS-919373	2	IRAK4
R-406	2	IRAK4
EMAVUSERTIB	2	IRAK4
BI-2536	2	IRAK4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IRAK4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03815357	Not specified	COMPLETED	What is the Incidence of an Immune Disorder in Children With Invasive Pneumococcal Disease (IPD)?