severe combined immunodeficiency due to IKK2 deficiency

Summary

severe combined immunodeficiency due to IKK2 deficiency (MONDO:0014267) is a disease caused by IKBKB (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IKBKB (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 758

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency due to IKK2 deficiency
Mondo ID	MONDO:0014267
OMIM	615592
Orphanet	397787
DOID	DOID:0111959
UMLS	C4747743
MedGen	1648569
GARD	0017641
Is cancer (heuristic)	no

Also known as: IMD15 · immunodeficiency 15 · immunodeficiency 15B · immunodeficiency type 15 · SCID due to IKK2 deficiency

Data availability: 758 ClinVar variants · 4 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 › combined immunodeficiency › severe combined immunodeficiency › T+ B+ severe combined immunodeficiency › severe combined immunodeficiency due to IKK2 deficiency

Related subtypes (1): severe combined immunodeficiency due to CARD11 deficiency

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

600 retrieved; paginated sample, class counts are floors:

390 likely benign, 170 uncertain significance, 16 pathogenic, 11 benign, 7 likely pathogenic, 6 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
102445	NM_001556.3(IKBKB):c.1292dup (p.Gln432fs)	IKBKB	Pathogenic	no assertion criteria provided
1357742	NM_001556.3(IKBKB):c.163C>T (p.Arg55Ter)	IKBKB	Pathogenic	criteria provided, single submitter
1388684	NM_001556.3(IKBKB):c.1927_1928del (p.Val643fs)	IKBKB	Pathogenic	criteria provided, single submitter
1433844	NM_001556.3(IKBKB):c.1705G>T (p.Glu569Ter)	IKBKB	Pathogenic	criteria provided, single submitter
1451255	NM_001556.3(IKBKB):c.1731dup (p.Pro578fs)	IKBKB	Pathogenic	criteria provided, single submitter
1453689	NM_001556.3(IKBKB):c.25del (p.Thr9fs)	IKBKB	Pathogenic	criteria provided, single submitter
157663	NM_001556.3(IKBKB):c.814C>T (p.Arg272Ter)	IKBKB	Pathogenic	criteria provided, single submitter
2080261	NM_001556.3(IKBKB):c.1609del (p.Arg536_Met537insTer)	IKBKB	Pathogenic	criteria provided, single submitter
2096950	NM_001556.3(IKBKB):c.1762C>T (p.Gln588Ter)	IKBKB	Pathogenic	criteria provided, single submitter
2131114	NM_001556.3(IKBKB):c.1392C>A (p.Cys464Ter)	IKBKB	Pathogenic	criteria provided, single submitter
2696833	NM_001556.3(IKBKB):c.1696C>T (p.Gln566Ter)	IKBKB	Pathogenic	criteria provided, single submitter
2768865	NM_001556.3(IKBKB):c.2116del (p.Glu706fs)	IKBKB	Pathogenic	criteria provided, single submitter
2844327	NM_001556.3(IKBKB):c.1847_1848del (p.Val616fs)	IKBKB	Pathogenic	criteria provided, single submitter
2856021	NM_001556.3(IKBKB):c.1429C>T (p.Gln477Ter)	IKBKB	Pathogenic	criteria provided, single submitter
3006118	NM_001556.3(IKBKB):c.1735C>T (p.Arg579Ter)	IKBKB	Pathogenic	criteria provided, single submitter
3245532	NC_000008.10:g.(?42146132)(42146266_?)del	IKBKB	Pathogenic	criteria provided, single submitter
2749018	NM_001556.3(IKBKB):c.1365-2A>C	IKBKB	Likely pathogenic	criteria provided, single submitter
3064957	NM_001556.3(IKBKB):c.923dup (p.Asn308fs)	IKBKB	Likely pathogenic	criteria provided, single submitter
3384120	NM_001556.3(IKBKB):c.849G>A (p.Trp283Ter)	IKBKB	Likely pathogenic	criteria provided, single submitter
3595616	NM_001556.3(IKBKB):c.229C>T (p.Arg77Ter)	IKBKB	Likely pathogenic	criteria provided, single submitter
3651056	NM_001556.3(IKBKB):c.567+1G>A	IKBKB	Likely pathogenic	criteria provided, single submitter
3779760	NM_001556.3(IKBKB):c.2115-1G>A	IKBKB	Likely pathogenic	criteria provided, single submitter
4071522	NM_001556.3(IKBKB):c.201-1G>A	IKBKB	Likely pathogenic	criteria provided, single submitter
1032752	NM_001556.3(IKBKB):c.887C>T (p.Pro296Leu)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299294	NM_001556.3(IKBKB):c.987G>A (p.Glu329=)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1574019	NM_001556.3(IKBKB):c.1031C>T (p.Thr344Met)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1938026	NM_001556.3(IKBKB):c.105+8C>T	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500043	NM_001556.3(IKBKB):c.1342C>T (p.Gln448Ter)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
422583	NM_001556.3(IKBKB):c.512A>G (p.Lys171Arg)	IKBKB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424198	NC_000008.10:g.(?41518984)(42698237_?)dup	ANK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
ANK1	Orphanet:251066	8p11.2 deletion syndrome
ANK1	Orphanet:822	Hereditary spherocytosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

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
FNTA	HGNC:3782	ENSG00000168522	P49354	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	clinvar
ANK1	HGNC:492	ENSG00000029534	P16157	Ankyrin-1	clinvar
AP3M2	HGNC:570	ENSG00000070718	P53677	AP-3 complex subunit mu-2	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.
FNTA	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex.
ANK1	Ankyrin-1	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.
AP3M2	AP-3 complex subunit mu-2	Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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	6.9×	0.392
Scaffold/PPI	1	4.3×	0.392
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

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
FNTA	Enzyme (other)	yes	2.5.1.58	Prenyl_trans_a
ANK1	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
AP3M2	Other/Unknown	no		Clathrin_mu, Longin-like_dom_sf, Clathrin_mu_CS

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
lower esophagus mucosa	1
spleen	1
esophagus squamous epithelium	1
gingival epithelium	1
olfactory bulb	1
body of tongue	1
skeletal muscle tissue of rectus abdominis	1
triceps brachii	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IKBKB	288	ubiquitous	marker	spleen, granulocyte, lower esophagus mucosa
FNTA	298	ubiquitous	marker	esophagus squamous epithelium, gingival epithelium, olfactory bulb
ANK1	226	broad	marker	skeletal muscle tissue of rectus abdominis, triceps brachii, body of tongue
AP3M2	273	ubiquitous	marker	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK1	5,705
IKBKB	5,421
FNTA	1,080
AP3M2	928

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANK1	P16157	21
FNTA	P49354	14
IKBKB	O14920	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AP3M2	P53677	93.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 4 evidence-associated genes (3 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 3 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	1268.9×	0.014	IKBKB
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)	1	1268.9×	0.014	IKBKB
SLC15A4:TASL-dependent IRF5 activation	1	634.4×	0.014	IKBKB
NrCAM interactions	1	543.8×	0.014	ANK1
IkBA variant leads to EDA-ID	1	543.8×	0.014	IKBKB
Neurofascin interactions	1	475.8×	0.014	ANK1
CHL1 interactions	1	423.0×	0.014	ANK1
GBP-mediated host defense	1	346.1×	0.014	FNTA
p75NTR recruits signalling complexes	1	292.8×	0.014	IKBKB
NF-kB is activated and signals survival	1	292.8×	0.014	IKBKB
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	292.8×	0.014	IKBKB
IRAK1 recruits IKK complex	1	271.9×	0.014	IKBKB
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	271.9×	0.014	IKBKB
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	237.9×	0.014	IKBKB
RIP-mediated NFkB activation via ZBP1	1	223.9×	0.014	IKBKB
Regulation of NF-kappa B signaling	1	211.5×	0.014	IKBKB
TICAM1, RIP1-mediated IKK complex recruitment	1	200.3×	0.014	IKBKB
Modulation of host responses by IFN-stimulated genes	1	200.3×	0.014	IKBKB
IKK complex recruitment mediated by RIP1	1	165.5×	0.015	IKBKB
Apoptotic cleavage of cellular proteins	1	158.6×	0.015	FNTA
RAS processing	1	158.6×	0.015	FNTA
TRAF6 mediated NF-kB activation	1	152.3×	0.015	IKBKB
Interaction between L1 and Ankyrins	1	122.8×	0.017	ANK1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.017	IKBKB
TNFR1-induced NF-kappa-B signaling pathway	1	112.0×	0.017	IKBKB
NOD1/2 Signaling Pathway	1	105.7×	0.017	IKBKB
Inactivation, recovery and regulation of the phototransduction cascade	1	105.7×	0.017	FNTA
TAK1-dependent IKK and NF-kappa-B activation	1	100.2×	0.018	IKBKB
Regulation of TNFR1 signaling	1	74.6×	0.023	IKBKB
Activation of NF-kappaB in B cells	1	65.6×	0.025	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide pheromone maturation	1	4213.0×	0.009	FNTA
protein farnesylation	1	1404.3×	0.009	FNTA
antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent	1	1053.2×	0.009	IKBKB
synaptic vesicle coating	1	842.6×	0.009	AP3M2
negative regulation of bicellular tight junction assembly	1	842.6×	0.009	IKBKB
protein geranylgeranylation	1	702.2×	0.009	FNTA
regulation of microtubule-based movement	1	702.2×	0.009	FNTA
clathrin-coated vesicle cargo loading, AP-3-mediated	1	601.9×	0.009	AP3M2
maintenance of epithelial cell apical/basal polarity	1	601.9×	0.009	ANK1
skeletal muscle acetylcholine-gated channel clustering	1	468.1×	0.009	FNTA
regulation of establishment of endothelial barrier	1	468.1×	0.009	IKBKB
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	468.1×	0.009	FNTA
protein localization to plasma membrane	2	54.4×	0.009	IKBKB, ANK1
regulation of toll-like receptor signaling pathway	1	383.0×	0.009	IKBKB
TRIF-dependent toll-like receptor signaling pathway	1	383.0×	0.009	IKBKB
synaptic vesicle recycling	1	300.9×	0.011	AP3M2
toll-like receptor 3 signaling pathway	1	280.9×	0.011	IKBKB
anterograde synaptic vesicle transport	1	247.8×	0.012	AP3M2
MyD88-dependent toll-like receptor signaling pathway	1	234.1×	0.012	IKBKB
interleukin-1-mediated signaling pathway	1	200.6×	0.012	IKBKB
stimulatory C-type lectin receptor signaling pathway	1	183.2×	0.012	IKBKB
Fc-epsilon receptor signaling pathway	1	183.2×	0.012	IKBKB
regulation of tumor necrosis factor-mediated signaling pathway	1	175.5×	0.012	IKBKB
stress-activated MAPK cascade	1	175.5×	0.012	IKBKB
positive regulation of Rac protein signal transduction	1	162.0×	0.013	FNTA
anterograde axonal transport	1	145.3×	0.014	AP3M2
Rac protein signal transduction	1	140.4×	0.014	FNTA
peptidyl-serine phosphorylation	1	123.9×	0.015	IKBKB
negative regulation of cytokine production involved in inflammatory response	1	105.3×	0.017	IKBKB
canonical NF-kappaB signal transduction	1	91.6×	0.019	IKBKB

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
FNTA	CORTISONE ACETATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IKBKB	16	4
FNTA	6	4
ANK1	0	0
AP3M2	0	0

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
CORTISONE ACETATE	4	FNTA
LONAFARNIB	4	FNTA
LESTAURTINIB	3	IKBKB
TIPIFARNIB	3	FNTA
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
L-778123 FREE BASE	1	FNTA
GGTI-2418	1	FNTA
BMS-214662	1	FNTA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
IKBKB	855	Binding:839, Functional:11, ADMET:5
FNTA	513	Binding:438, Functional:75

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IKBKB	2.7.11.10	IkappaB kinase
FNTA	2.5.1.58, 2.5.1.59	protein farnesyltransferase, protein geranylgeranyltransferase type I

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
IKBKB	855
FNTA	513

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

22 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
CORTISONE ACETATE	4	FNTA
LONAFARNIB	4	FNTA
LESTAURTINIB	3	IKBKB
TIPIFARNIB	3	FNTA
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
L-778123 FREE BASE	1	FNTA
GGTI-2418	1	FNTA
BMS-214662	1	FNTA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	IKBKB, FNTA
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	2	ANK1, AP3M2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANK1	0	—
AP3M2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.