Immunodeficiency 15a

Summary

Immunodeficiency 15a (MONDO:0032599) is a disease caused by IKBKB (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: IKBKB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 15a
Mondo ID	MONDO:0032599
OMIM	618204
Orphanet	700205
DOID	DOID:0111960
UMLS	C4748694
MedGen	1648385
GARD	0018469
Is cancer (heuristic)	no

Also known as: IMD15A

Data availability: 15 ClinVar variants · 5 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 15a

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, immunodeficiency 67, 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 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

15 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 2 pathogenic, 2 conflicting classifications of pathogenicity, 2 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
157663	NM_001556.3(IKBKB):c.814C>T (p.Arg272Ter)	IKBKB	Pathogenic	criteria provided, single submitter
590941	NM_001556.3(IKBKB):c.607G>A (p.Val203Ile)	IKBKB	Pathogenic	criteria provided, multiple submitters, no conflicts
3595616	NM_001556.3(IKBKB):c.229C>T (p.Arg77Ter)	IKBKB	Likely pathogenic	criteria provided, single submitter
2500043	NM_001556.3(IKBKB):c.1342C>T (p.Gln448Ter)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547914	NM_001556.3(IKBKB):c.2087A>G (p.Asn696Ser)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027942	NM_001556.3(IKBKB):c.313C>T (p.Arg105Trp)	IKBKB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1056391	NM_001556.3(IKBKB):c.1654A>G (p.Met552Val)	IKBKB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1351267	NM_001556.3(IKBKB):c.1424T>C (p.Met475Thr)	IKBKB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1801826	NM_001556.3(IKBKB):c.1465A>G (p.Ser489Gly)	IKBKB	Uncertain significance	criteria provided, single submitter
2166403	NM_001556.3(IKBKB):c.1173C>A (p.Asp391Glu)	IKBKB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2414337	NM_001556.3(IKBKB):c.1600G>A (p.Val534Ile)	IKBKB	Uncertain significance	criteria provided, multiple submitters, no conflicts
3109005	NM_001556.3(IKBKB):c.395C>T (p.Ala132Val)	IKBKB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1801352	NM_001556.3(IKBKB):c.368T>C (p.Leu123Pro)	LOC126860373	Uncertain significance	criteria provided, multiple submitters, no conflicts
402969	NM_001556.3(IKBKB):c.1240+14A>T	IKBKB	Benign	criteria provided, multiple submitters, no conflicts
708040	NM_001556.3(IKBKB):c.2128G>A (p.Ala710Thr)	IKBKB	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
IKBKB	Strong	Autosomal recessive	immunodeficiency 15a	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IKBKB	Orphanet:397787	Combined immunodeficiency due to IKBKB deficiency
IKBKB	Orphanet:700205	Combined immunodeficiency due to IKBKB gain-of-function mutation

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
IKBKB	HGNC:5960	ENSG00000104365	O14920	Inhibitor of nuclear factor kappa-B kinase subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IKBKB	Inhibitor of nuclear factor kappa-B kinase subunit beta	Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses.

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)
IKBKB	Kinase	yes	2.7.11.10	Ubiquitin-like_dom, Prot_kinase_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

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
granulocyte	1
lower esophagus mucosa	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IKBKB	288	ubiquitous	marker	spleen, granulocyte, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IKBKB	5,421

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IKBKB	O14920	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
IKBKB deficiency causes SCID	1	3806.7×	0.003	IKBKB
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)	1	3806.7×	0.003	IKBKB
SLC15A4:TASL-dependent IRF5 activation	1	1903.3×	0.003	IKBKB
IkBA variant leads to EDA-ID	1	1631.4×	0.003	IKBKB
p75NTR recruits signalling complexes	1	878.5×	0.003	IKBKB
NF-kB is activated and signals survival	1	878.5×	0.003	IKBKB
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	878.5×	0.003	IKBKB
IRAK1 recruits IKK complex	1	815.7×	0.003	IKBKB
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	815.7×	0.003	IKBKB
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	713.8×	0.003	IKBKB
RIP-mediated NFkB activation via ZBP1	1	671.8×	0.003	IKBKB
Regulation of NF-kappa B signaling	1	634.4×	0.003	IKBKB
TICAM1, RIP1-mediated IKK complex recruitment	1	601.0×	0.003	IKBKB
Modulation of host responses by IFN-stimulated genes	1	601.0×	0.003	IKBKB
IKK complex recruitment mediated by RIP1	1	496.5×	0.004	IKBKB
TRAF6 mediated NF-kB activation	1	456.8×	0.004	IKBKB
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.005	IKBKB
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.005	IKBKB
NOD1/2 Signaling Pathway	1	317.2×	0.005	IKBKB
TAK1-dependent IKK and NF-kappa-B activation	1	300.5×	0.005	IKBKB
Regulation of TNFR1 signaling	1	223.9×	0.006	IKBKB
Activation of NF-kappaB in B cells	1	196.9×	0.007	IKBKB
FCERI mediated NF-kB activation	1	156.4×	0.008	IKBKB
CLEC7A (Dectin-1) signaling	1	142.8×	0.008	IKBKB
PKR-mediated signaling	1	141.0×	0.008	IKBKB
ER-Phagosome pathway	1	129.8×	0.008	IKBKB
Downstream TCR signaling	1	128.3×	0.008	IKBKB
Interleukin-1 signaling	1	124.1×	0.008	IKBKB
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.011	IKBKB

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
antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent	1	4213.0×	0.004	IKBKB
negative regulation of bicellular tight junction assembly	1	3370.4×	0.004	IKBKB
regulation of establishment of endothelial barrier	1	1872.4×	0.004	IKBKB
regulation of toll-like receptor signaling pathway	1	1532.0×	0.004	IKBKB
TRIF-dependent toll-like receptor signaling pathway	1	1532.0×	0.004	IKBKB
toll-like receptor 3 signaling pathway	1	1123.5×	0.004	IKBKB
MyD88-dependent toll-like receptor signaling pathway	1	936.2×	0.004	IKBKB
interleukin-1-mediated signaling pathway	1	802.5×	0.004	IKBKB
stimulatory C-type lectin receptor signaling pathway	1	732.7×	0.004	IKBKB
Fc-epsilon receptor signaling pathway	1	732.7×	0.004	IKBKB
regulation of tumor necrosis factor-mediated signaling pathway	1	702.2×	0.004	IKBKB
stress-activated MAPK cascade	1	702.2×	0.004	IKBKB
peptidyl-serine phosphorylation	1	495.6×	0.005	IKBKB
negative regulation of cytokine production involved in inflammatory response	1	421.3×	0.005	IKBKB
canonical NF-kappaB signal transduction	1	366.4×	0.006	IKBKB
tumor necrosis factor-mediated signaling pathway	1	330.4×	0.006	IKBKB
negative regulation of autophagy	1	259.3×	0.007	IKBKB
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.008	IKBKB
protein maturation	1	163.6×	0.009	IKBKB
cellular response to tumor necrosis factor	1	163.6×	0.009	IKBKB
integrin-mediated signaling pathway	1	160.5×	0.009	IKBKB
T cell receptor signaling pathway	1	151.8×	0.009	IKBKB
response to virus	1	144.0×	0.009	IKBKB
autophagy	1	110.1×	0.011	IKBKB
protein localization to plasma membrane	1	108.7×	0.011	IKBKB
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	IKBKB
protein phosphorylation	1	68.0×	0.017	IKBKB
inflammatory response	1	37.7×	0.029	IKBKB
innate immune response	1	33.6×	0.032	IKBKB
positive regulation of DNA-templated transcription	1	27.9×	0.037	IKBKB

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
IKBKB	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IKBKB	16	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	IKBKB
RUXOLITINIB	4	IKBKB
DIOSMIN	4	IKBKB
DEXAMETHASONE	4	IKBKB
CRIZOTINIB	4	IKBKB
MIDOSTAURIN	4	IKBKB
LESTAURTINIB	3	IKBKB
SU-014813	2	IKBKB
ERTIPROTAFIB	2	IKBKB
TAK-715	2	IKBKB
R-406	2	IKBKB
ELLAGIC ACID	2	IKBKB
AS-602868	1	IKBKB
KW-2449	1	IKBKB
IMD-0354	1	IKBKB
AST-487	1	IKBKB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
IKBKB	855	Binding:839, Functional:11, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IKBKB	2.7.11.10	IkappaB kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
IKBKB	855

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

16 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)
FEDRATINIB	4	IKBKB
RUXOLITINIB	4	IKBKB
DIOSMIN	4	IKBKB
DEXAMETHASONE	4	IKBKB
CRIZOTINIB	4	IKBKB
MIDOSTAURIN	4	IKBKB
LESTAURTINIB	3	IKBKB
SU-014813	2	IKBKB
ERTIPROTAFIB	2	IKBKB
TAK-715	2	IKBKB
R-406	2	IKBKB
ELLAGIC ACID	2	IKBKB
AS-602868	1	IKBKB
KW-2449	1	IKBKB
IMD-0354	1	IKBKB
AST-487	1	IKBKB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IKBKB
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: 0.