Immunodeficiency, common variable, 12

disease

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Also known as common variable immunodeficiency caused by mutation in NFKB1CVID12immunodeficiency, common variable, type 12NFKB1 common variable immunodeficiency

Summary

Immunodeficiency, common variable, 12 (MONDO:0014697) is a disease caused by NFKB1 (GenCC Strong), with 3 cohort genes.

At a glance

Causal gene: NFKB1 (GenCC Strong)
Cohort genes: 3
ClinVar variants: 86

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 12
Mondo ID	MONDO:0014697
OMIM	616576
Orphanet	696874
DOID	DOID:0081154
UMLS	C4225277
MedGen	906018
GARD	0016141
Is cancer (heuristic)	no

Also known as: common variable immunodeficiency caused by mutation in NFKB1 · CVID12 · immunodeficiency, common variable, 12 · immunodeficiency, common variable, type 12 · NFKB1 common variable immunodeficiency

Data availability: 86 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › immunodeficiency, common variable, 12

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

86 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 18 likely pathogenic, 12 pathogenic, 8 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 7 benign, 4 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3377098	NM_003998.4(NFKB1):c.1676_1679delinsCTTAC (p.Leu559fs)	LOC126807127	Pathogenic	criteria provided, single submitter
1027409	NM_003998.4(NFKB1):c.418_427del (p.Leu140fs)	NFKB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1064676	NM_003998.4(NFKB1):c.139del (p.Ile47fs)	NFKB1	Pathogenic	no assertion criteria provided
1064678	NM_003998.4(NFKB1):c.469C>T (p.Arg157Ter)	NFKB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1064682	NM_003998.4(NFKB1):c.1012del (p.Ser338fs)	NFKB1	Pathogenic	no assertion criteria provided
1685980	NM_003998.4(NFKB1):c.407+2T>G	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210057	NM_003998.4(NFKB1):c.835+2T>G	NFKB1	Pathogenic	no assertion criteria provided
210058	NM_003998.4(NFKB1):c.465dup (p.Ala156fs)	NFKB1	Pathogenic	no assertion criteria provided
2431615	NM_003998.4(NFKB1):c.1075G>T (p.Glu359Ter)	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3901213	NM_003998.4(NFKB1):c.2228del	NFKB1	Pathogenic	criteria provided, single submitter
430907	NM_003998.4(NFKB1):c.904dup (p.Ser302fs)	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813539	NM_003998.4(NFKB1):c.846del (p.Ile283fs)	NFKB1	Pathogenic	criteria provided, single submitter
623198	NM_003998.4(NFKB1):c.317dup (p.Asn106fs)	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
636403	NM_003998.4(NFKB1):c.1402C>T (p.Gln468Ter)	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
827719	NM_003998.4(NFKB1):c.260T>G (p.Ile87Ser)	NFKB1	Pathogenic	criteria provided, single submitter
827724	NM_003998.4(NFKB1):c.1539_1543del (p.His513fs)	NFKB1	Pathogenic	criteria provided, single submitter
827726	NM_003998.4(NFKB1):c.850C>T (p.Arg284Ter)	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871105	NM_003998.4(NFKB1):c.407+1G>A	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976031	NM_003998.4(NFKB1):c.159+1G>A	NFKB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982698	NM_003998.4(NFKB1):c.522_525dup (p.Leu176Ter)	NFKB1	Pathogenic	criteria provided, single submitter
4820140	NM_003998.4(NFKB1):c.1750C>T (p.Gln584Ter)	LOC126807127	Likely pathogenic	criteria provided, single submitter
623199	NM_003998.4(NFKB1):c.1752+1G>A	LOC126807127	Likely pathogenic	criteria provided, single submitter
1697314	NM_003998.4:c.(927+1_928-1)_(1066+1_1067-1)del	NFKB1	Likely pathogenic	criteria provided, single submitter
1698926	NM_003998.4(NFKB1):c.2227+1G>A	NFKB1	Likely pathogenic	criteria provided, single submitter
1702987	NM_003998.4(NFKB1):c.988G>A (p.Val330Met)	NFKB1	Likely pathogenic	no assertion criteria provided
1803239	NM_003998.4(NFKB1):c.2353-1G>A	NFKB1	Likely pathogenic	criteria provided, single submitter
210056	NM_003998.4(NFKB1):c.730+4A>G	NFKB1	Likely pathogenic	criteria provided, single submitter
3065330	NM_003998.4(NFKB1):c.1753-1G>T	NFKB1	Likely pathogenic	criteria provided, single submitter
3068256	NM_003998.4(NFKB1):c.2240del (p.Leu747fs)	NFKB1	Likely pathogenic	criteria provided, single submitter
3242029	NM_003998.4(NFKB1):c.927+2T>C	NFKB1	Likely 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
NFKB1	Strong	Autosomal dominant	immunodeficiency, common variable, 12	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NFKB1	Orphanet:696874	NFKB1-related immune dysregulation

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NFKB1	HGNC:7794	ENSG00000109320	P19838	Nuclear factor NF-kappa-B p105 subunit	gencc,clinvar
NFKBID	HGNC:15671	ENSG00000167604	Q8NI38	NF-kappa-B inhibitor delta	clinvar
SLC9B1	HGNC:24244	ENSG00000164037	Q4ZJI4	Sodium/hydrogen exchanger 9B1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NFKB1	Nuclear factor NF-kappa-B p105 subunit	NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as infl…
NFKBID	NF-kappa-B inhibitor delta	Regulates the expression of IL-2, IL-6, and other cytokines through regulation on NF-kappa-B activity.
SLC9B1	Sodium/hydrogen exchanger 9B1	Sperm-specific Na(+)/H(+) exchanger involved in intracellular pH regulation of spermatozoa.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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
Transporter	1	25.9×	0.114
Scaffold/PPI	1	5.8×	0.246
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
NFKB1	Transcription factor	no	NFkB/Dor, Death_dom, Ankyrin_rpt
NFKBID	Scaffold/PPI	no	Ankyrin_rpt, Ankyrin_rpt-contain_sf
SLC9B1	Transporter	yes	Cation/H_exchanger_TM, Na+/solute_symporter_sf, CPA1_transporter

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cartilage tissue	1
endometrium epithelium	1
bone marrow cell	1
granulocyte	1
sural nerve	1
left testis	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NFKB1	252	ubiquitous	marker	endometrium epithelium, cartilage tissue, calcaneal tendon
NFKBID	169	ubiquitous	marker	bone marrow cell, granulocyte, sural nerve
SLC9B1	161	broad	marker	sperm, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFKB1	10,484
NFKBID	1,750
SLC9B1	589

Intra-cohort edges

A	B	Sources
NFKB1	NFKBID	biogrid_interaction, intact, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NFKB1	P19838	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NFKBID	Q8NI38	88.20
SLC9B1	Q4ZJI4	79.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CLEC7A/inflammasome pathway	1	951.7×	0.010	NFKB1
DEx/H-box helicases activate type I IFN and inflammatory cytokines production	1	815.7×	0.010	NFKB1
IkBA variant leads to EDA-ID	1	815.7×	0.010	NFKB1
Regulation of NFE2L2 gene expression	1	713.8×	0.010	NFKB1
Interleukin-1 processing	1	634.4×	0.010	NFKB1
Regulated proteolysis of p75NTR	1	519.1×	0.010	NFKB1
NF-kB is activated and signals survival	1	439.2×	0.010	NFKB1
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	356.9×	0.010	NFKB1
RIP-mediated NFkB activation via ZBP1	1	335.9×	0.010	NFKB1
The NLRP3 inflammasome	1	335.9×	0.010	NFKB1
CD209 (DC-SIGN) signaling	1	259.6×	0.011	NFKB1
TRAF6 mediated NF-kB activation	1	228.4×	0.012	NFKB1
Purinergic signaling in leishmaniasis infection	1	211.5×	0.012	NFKB1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.013	NFKB1
TAK1-dependent IKK and NF-kappa-B activation	1	150.3×	0.014	NFKB1
SARS-CoV-1 activates/modulates innate immune responses	1	135.9×	0.014	NFKB1
Transcriptional Regulation by VENTX	1	132.8×	0.014	NFKB1
Activation of NF-kappaB in B cells	1	98.5×	0.018	NFKB1
Activation of STAT3 by cadherin engagement	1	81.6×	0.019	NFKB1
PKMTs methylate histone lysines	1	80.4×	0.019	NFKB1
FCERI mediated NF-kB activation	1	78.2×	0.019	NFKB1
CLEC7A (Dectin-1) signaling	1	71.4×	0.020	NFKB1
Stimuli-sensing channels	1	68.0×	0.020	SLC9B1
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.020	NFKB1
Downstream TCR signaling	1	64.2×	0.020	NFKB1
Interleukin-1 signaling	1	62.1×	0.020	NFKB1
Regulation of PD-L1(CD274) transcription	1	54.4×	0.022	NFKB1
Senescence-Associated Secretory Phenotype (SASP)	1	49.6×	0.023	NFKB1
Ion channel transport	1	48.0×	0.023	SLC9B1
HCMV Early Events	1	40.5×	0.026	NFKB1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of T-helper 17 cell differentiation	1	1872.4×	0.008	NFKBID
positive regulation of miRNA metabolic process	1	1872.4×	0.008	NFKB1
negative regulation of vitamin D biosynthetic process	1	1404.3×	0.008	NFKB1
positive regulation of hyaluronan biosynthetic process	1	1404.3×	0.008	NFKB1
cellular response to dsRNA	1	1123.5×	0.008	NFKB1
mammary gland involution	1	936.2×	0.008	NFKB1
cellular response to interleukin-17	1	802.5×	0.008	NFKB1
cellular response to nicotine	1	702.2×	0.008	NFKB1
antibacterial innate immune response	1	510.7×	0.009	NFKB1
positive regulation of lipid storage	1	468.1×	0.009	NFKB1
inflammatory response	2	25.1×	0.009	NFKB1, NFKBID
negative regulation of interleukin-12 production	1	351.1×	0.009	NFKB1
cellular response to interleukin-6	1	330.4×	0.009	NFKB1
obsolete inorganic cation transmembrane transport	1	312.1×	0.009	SLC9B1
cellular response to angiotensin	1	312.1×	0.009	NFKB1
positive regulation of macrophage derived foam cell differentiation	1	280.9×	0.009	NFKB1
non-canonical NF-kappaB signal transduction	1	280.9×	0.009	NFKB1
response to muscle stretch	1	255.3×	0.010	NFKB1
positive regulation of cholesterol efflux	1	208.1×	0.011	NFKB1
regulation of intracellular pH	1	200.6×	0.011	SLC9B1
negative regulation of cytokine production involved in inflammatory response	1	140.4×	0.015	NFKB1
B cell receptor signaling pathway	1	133.8×	0.015	NFKB1
canonical NF-kappaB signal transduction	1	122.1×	0.016	NFKB1
tumor necrosis factor-mediated signaling pathway	1	110.1×	0.017	NFKB1
JNK cascade	1	90.6×	0.019	NFKB1
positive regulation of transcription initiation by RNA polymerase II	1	90.6×	0.019	NFKB1
cellular response to mechanical stimulus	1	72.0×	0.023	NFKB1
monoatomic ion transmembrane transport	1	69.3×	0.023	SLC9B1
cellular response to virus	1	66.9×	0.023	NFKB1
single fertilization	1	61.1×	0.024	SLC9B1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
NFKB1	INDOPROFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NFKB1	152	4
NFKBID	0	0
SLC9B1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INDOPROFEN	4	NFKB1
VAMOROLONE	4	NFKB1
BORTEZOMIB	4	NFKB1
DEXAMETHASONE	4	NFKB1
SULFASALAZINE	4	NFKB1
LEVOSALBUTAMOL	4	NFKB1
CLOTRIMAZOLE	4	NFKB1
GLIPIZIDE	4	NFKB1
SALMETEROL XINAFOATE	4	NFKB1
PHENELZINE	4	NFKB1
SULFAPHENAZOLE	4	NFKB1
AMOXAPINE	4	NFKB1
PROPANTHELINE	4	NFKB1
DECAMETHONIUM	4	NFKB1
NICARDIPINE HYDROCHLORIDE	4	NFKB1
PHENTOLAMINE MESYLATE	4	NFKB1
PHENYLEPHRINE	4	NFKB1
CARISOPRODOL	4	NFKB1
AZELAIC ACID	4	NFKB1
CARBETAPENTANE CITRATE	4	NFKB1
NIALAMIDE	4	NFKB1
EPINEPHRINE BITARTRATE	4	NFKB1
NILUTAMIDE	4	NFKB1
BUDESONIDE	4	NFKB1
ESTRONE	4	NFKB1
METHAPYRILENE	4	NFKB1
PIMOZIDE	4	NFKB1
TRIAMCINOLONE	4	NFKB1
BISOPROLOL FUMARATE	4	NFKB1
AZACITIDINE	4	NFKB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NFKB1	256	Binding:249, Functional:7

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NFKB1	256

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
INDOPROFEN	4	NFKB1
VAMOROLONE	4	NFKB1
BORTEZOMIB	4	NFKB1
DEXAMETHASONE	4	NFKB1
SULFASALAZINE	4	NFKB1
LEVOSALBUTAMOL	4	NFKB1
CLOTRIMAZOLE	4	NFKB1
GLIPIZIDE	4	NFKB1
SALMETEROL XINAFOATE	4	NFKB1
PHENELZINE	4	NFKB1
SULFAPHENAZOLE	4	NFKB1
AMOXAPINE	4	NFKB1
PROPANTHELINE	4	NFKB1
DECAMETHONIUM	4	NFKB1
NICARDIPINE HYDROCHLORIDE	4	NFKB1
PHENTOLAMINE MESYLATE	4	NFKB1
PHENYLEPHRINE	4	NFKB1
CARISOPRODOL	4	NFKB1
AZELAIC ACID	4	NFKB1
CARBETAPENTANE CITRATE	4	NFKB1
NIALAMIDE	4	NFKB1
EPINEPHRINE BITARTRATE	4	NFKB1
NILUTAMIDE	4	NFKB1
BUDESONIDE	4	NFKB1
ESTRONE	4	NFKB1
METHAPYRILENE	4	NFKB1
PIMOZIDE	4	NFKB1
TRIAMCINOLONE	4	NFKB1
BISOPROLOL FUMARATE	4	NFKB1
AZACITIDINE	4	NFKB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NFKB1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC9B1
E	Difficult family or no structure, no drug	1	NFKBID

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)
NFKBID	0	—
SLC9B1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: NFKB1, NFKBID, SLC9B1