NFKBIA

Summary

NFKBIA (NFKB inhibitor alpha, HGNC:7797) is a protein-coding gene on chromosome 14q13.2, encoding NF-kappa-B inhibitor alpha (P25963). Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals.

This gene encodes a member of the NF-kappa-B inhibitor family, which contain multiple ankrin repeat domains. The encoded protein interacts with REL dimers to inhibit NF-kappa-B/REL complexes which are involved in inflammatory responses. The encoded protein moves between the cytoplasm and the nucleus via a nuclear localization signal and CRM1-mediated nuclear export. Mutations in this gene have been found in ectodermal dysplasia anhidrotic with T-cell immunodeficiency autosomal dominant disease.

Source: NCBI Gene 4792 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ectodermal dysplasia and immunodeficiency 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 33
• Clinical variants (ClinVar): 341 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• Transcription factor: yes — 119 downstream targets (CollecTRI)
• MANE Select transcript: NM_020529

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7797
Approved symbol	NFKBIA
Name	NFKB inhibitor alpha
Location	14q13.2
Locus type	gene with protein product
Status	Approved
Aliases	IKBA, MAD-3, IkappaBalpha
Ensembl gene	ENSG00000100906
Ensembl biotype	protein_coding
OMIM	164008
Entrez	4792

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 retained_intron, 8 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000216797, ENST00000553342, ENST00000554001, ENST00000555371, ENST00000555629, ENST00000556664, ENST00000557100, ENST00000557140, ENST00000557389, ENST00000557459, ENST00000697954, ENST00000697955, ENST00000697956, ENST00000697957, ENST00000697958, ENST00000697959, ENST00000697960, ENST00000697961, ENST00000697962, ENST00000697965, ENST00000697966, ENST00000860149, ENST00000960693

RefSeq mRNA: 1 — MANE Select: NM_020529 NM_020529

CCDS: CCDS9656

Canonical transcript exons

ENST00000216797 — 6 exons

Exon	Start	End
ENSE00000000035	35404418	35404749
ENSE00000889712	35401513	35402060
ENSE00002472965	35403690	35403798
ENSE00003972293	35402394	35402663
ENSE00003972297	35402771	35402859
ENSE00003972308	35403150	35403360

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 278.0636 / max 19582.0217, expressed in 1826 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142886	256.0502	1823
142877	8.6896	1163
142881	5.9321	1045
142880	1.9649	619
142878	1.3745	439
142883	0.8457	434
142876	0.7416	296
142879	0.7118	288
142884	0.6219	367
142887	0.5198	166

Top tissues by expression

302 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	99.90	gold quality
pericardium	UBERON:0002407	99.64	gold quality
lower lobe of lung	UBERON:0008949	99.60	gold quality
oocyte	CL:0000023	99.57	gold quality
nipple	UBERON:0002030	99.52	gold quality
saphenous vein	UBERON:0007318	99.47	gold quality
mucosa of urinary bladder	UBERON:0001259	99.46	gold quality
type B pancreatic cell	CL:0000169	99.40	gold quality
monocyte	CL:0000576	99.40	gold quality
right lung	UBERON:0002167	99.37	gold quality
upper lobe of lung	UBERON:0008948	99.37	gold quality
upper lobe of left lung	UBERON:0008952	99.37	gold quality
trachea	UBERON:0003126	99.35	gold quality
olfactory bulb	UBERON:0002264	99.27	gold quality
peripheral nervous system	UBERON:0000010	99.19	gold quality
tibial nerve	UBERON:0001323	99.19	gold quality
granulocyte	CL:0000094	99.18	gold quality
cartilage tissue	UBERON:0002418	99.18	gold quality
secondary oocyte	CL:0000655	99.17	gold quality
mononuclear cell	CL:0000842	99.16	gold quality
trigeminal ganglion	UBERON:0001675	99.12	gold quality
left uterine tube	UBERON:0001303	99.07	gold quality
leukocyte	CL:0000738	99.05	gold quality
spleen	UBERON:0002106	99.05	gold quality
pylorus	UBERON:0001166	99.04	gold quality
skin of abdomen	UBERON:0001416	99.03	gold quality
vermiform appendix	UBERON:0001154	99.02	gold quality
cardia of stomach	UBERON:0001162	99.02	gold quality
lower esophagus mucosa	UBERON:0035834	98.97	gold quality
right ovary	UBERON:0002118	98.94	gold quality

Single-cell (SCXA)

Detected in 38 experiment(s), a significant marker in 29.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	13234.83
E-HCAD-36	yes	10608.19
E-HCAD-23	yes	9326.43
E-HCAD-11	yes	8860.71
E-GEOD-149689	yes	6616.90
E-MTAB-9467	yes	5851.18
E-CURD-46	yes	5692.23
E-GEOD-76312	yes	4282.05
E-MTAB-8322	yes	4193.91
E-CURD-53	yes	3757.83
E-HCAD-15	yes	3643.36
E-CURD-122	yes	3612.79
E-MTAB-10042	yes	3489.88
E-CURD-88	yes	3462.58
E-MTAB-11011	yes	3172.80

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

119 targets.

Target	Regulation
ABCC8
ADAM2
AGT
AKT1
ANXA5
APOA1
AQP5
ARRB2
AXL
BANP
BCL2
BCL2L1
BIRC3
BMP2
C4B
CAST
CAT
CCL15
CCL2
CCL20
CCL3
CCL5	Repression
CCND1
CD40	Repression
CD58	Repression
CD83
CDKN1A
CDKN1C
CHUK
CNTN2

Upstream regulators (CollecTRI, top): AIRE, CEBPB, CTNNB1, DDRGK1, DNMT1, ESR2, FOS, FOXC1, HBP1, JUN, KLF6, KMT2A, KMT2B, MYC, NFKB1, NFKB2, NFKB, NFKBIA, NFKBID, NR3C1, NR4A1, PARP10, PGR, PPARA, PPARG, RBPJ, REL, RELA, RPS3, SMAD7, SP1, SPI1, SSRP1, TBP, TCF3, TFCP2, TP53, VDR, WNT5A, ZBTB20

miRNA regulators (miRDB)

49 targeting NFKBIA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-377-5P	99.70	65.28	712

Literature-anchored findings (GeneRIF, showing 40)

• IkappaBalpha x p53 complex plays an important role in responses involving growth regulation, apoptosis, and hypoxic stress (PMID:11799106)
• A novel in vitro assay for deubiquitination of I kappa B alpha (PMID:11913973)
• NF-kappa Beta activation in BAL cells may play in important role in initiation and progression of silica-induced pulmonary inflammation, cellular damage, and fibrosis (PMID:12028809)
• results demonstrate that SLPI prevents LPS-induced NF-kappaB activation by inhibiting degradation of IkappaBalpha without affecting the LPS-induced phosphorylation and ubiquitination of IkappaBalpha (PMID:12084717)
• Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C and Ikappab-alpha (PMID:12086926)
• The protein IkappaBalpha is a novel substrate of recombinant c-Abl in HEK cells. c-Abl-mediated phosphorylation at tyrosine 305 is associated with an increase of the IkappaBalpha protein stability. (PMID:12167702)
• A membrane-transducing mutant of I kappa B alpha has been generated that efficiently enters cells, associates with NF-kappa B p65 subunit, and inhibits NF-kappa B-mediated transcription and binding to its consensus sequence. (PMID:12193729)
• Increased nuclear accumulation of I kappa B alpha in neutrophils is associated with the inhibition of NF-kappa B activity and the induction of apoptosis in these cells. (PMID:12244195)
• NFkB, I-kB and I-kB kinase are present in platelets; upon platelet activation, the NF-kappaB/I-kappaBalpha complex is dissociated by phosphorylation of I-kB and proteolysis. (PMID:12297126)
• polymorphism associated with an increased risk of multiple myeloma (PMID:12377412)
• These data suggest that the subcellular location of I(kappa)B(alpha) is a critical determinant in ionizing radiation-induced nuclear factor-kappaB activation. (PMID:12388747)
• IkappaBalpha attenuates NF-kappaBeta transcriptional activity which is an important process that restores the latent state in post-induced cells (PMID:12419806)
• found in mitochondria; regulates mitochondrial gene expression (PMID:12433922)
• Our data suggest that the serine and tyrosine phosphorylation of IkappaB-alpha may play a role in determining the radiosensitivity of malignant glioma cells. (PMID:12518988)
• IkappaBalpha and p65 have roles in regulating the cytoplasmic shuttling of nuclear corepressors (PMID:12589049)
• data suggest that NO may play a major role in the regulation of IkappaBalpha levels in aortic endothelial cells and that the application of low shear flow increases NF-kappaB activity by attenuating NO generation and thus IkappaBalpha levels. (PMID:12620896)
• Data show that increased nuclear factor-kappaB (NF-kB) activity in the amnion during labor is associated with an increase in the expression of NF-kBp65 and of the NF-kB binding proteins IkBa, IkBb-1 and IkBb-2. (PMID:12651903)
• Induced stabilization of IkappaBalpha can facilitate its re-synthesis and prevent sequential degradation. (PMID:12704657)
• H2O2 induces NF-kappaB activation, not through serine phosphorylation or degradation of IkappaBalpha, but through Syk-mediated tyrosine phosphorylation of IkappaBalpha (PMID:12711606)
• results indicate that protein kinase CKII may control IkappaBalpha and p27Kip1 degradation and thereby G1/S phase transition through the phosphorylation of threonine 10 within CKBBP1 protein (PMID:12748192)
• IKBA is degraded by HSP27 through the 26s proteasome (PMID:12897149)
• Okadaic acid induces degradation of the nuclear IKBA in neutrophils. (PMID:12921778)
• Inhibitor kappa B-alpha promoter polymorphisms is associated with pulmonary sarcoidosis (PMID:12944982)
• IkappaBalpha regulates the transcriptional activity of homeodomain-containing proteins positively through cytoplasmic sequestration of HDAC1 and HDAC3 (PMID:12972430)
• single nucleotide polymorphisms in the 3’-UTR were significantly increased only in Crohn’s disease patients without a variation in the CARD15 gene. (PMID:13680285)
• IkappaBalpha was markedly degraded at 1 h, and NF-kappaB-DNA-binding activity markedly increased 2 h after beta(2) integrin aggregation (PMID:14576361)
• Down-regulation of PTEN by NIK/NF-kappaB results in activation of the PI3K/Akt pathway. This effect is associated with a lack of an inhibitor of kappaB (IkappaB)-alpha autoregulatory loop. (PMID:14623898)
• PCR measure of I kappa B-alpha mRNA levels is a rapid, sensitive, and powerful method to quantify the transcriptional power of NF-kappa B. (PMID:15068390)
• nuclear factor-kappa B and I kappa B alpha proteins have roles in development of prostatic adenocarcinomas (PMID:15073126)
• I kappa B-NF kappa B participates on ERK2-mediated survival mechanisms (PMID:15173174)
• IkappaBalpha is inhibited by ultraviolet rays and activates NFkappaB (PMID:15184376)
• Calpain plays an important role in IkB alpha degradation, a crucial event in T cell activation. (PMID:15202778)
• results indicate that the PKC pathway leading to SOD2 induction proceeds at least in part through NF-kappaB and that inhibition of IkappaBalpha synthesis might serve as a potential pharmacological approach to up-regulate MnSOD (PMID:15330761)
• IkappaBalpha mutation can result in different clinical syndromes within one family (PMID:15337789)
• demonstrated that TRAIL mediates the recruitment of PI-3K/Akt and NF-B/IB pathways in leukaemic cells, namely Jurkat T cells (PMID:15389633)
• IkappaBalpha is recruited to the promoter regions of the Notch-target gene, hes1 (PMID:15536134)
• IkappaB-alphaS32/36A, a proteolysis-resistant inhibitor of NF-kappaB, potently inhibits the growth of HIV-1 and SIVmac239 in cell cultures. (PMID:15613239)
• Results indicate that polymyxin B induces a partial maturation of human dendritic cells through increased adhesion and activation of the IkappaB-alpha/NF-kappaB pathway, and that increased ERK1/2 activation inhibits maturation. (PMID:15671028)
• gene transactivation by the transcription factor NF-kappaB is subject to the regulation of a dynamic balance between the coactivators and corepressors in the IkappaB alpha promoter (PMID:15811852)
• IkappaB-alpha is involved in the proliferation of human Burkitt lymphoma Daudi cells, possibly through the MAP kinase pathway. (PMID:15979856)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nfkbia	ENSMUSG00000021025
drosophila_melanogaster	cact	FBGN0000250
drosophila_melanogaster	iPLA2-VIA	FBGN0036053
drosophila_melanogaster	mask	FBGN0043884
caenorhabditis_elegans		WBGENE00011240
caenorhabditis_elegans		WBGENE00011423

Paralogs (4): NFKBIB (ENSG00000104825), ANKRD22 (ENSG00000152766), TONSL (ENSG00000160949), PLA2G6 (ENSG00000184381)

Protein

Protein identifiers

NF-kappa-B inhibitor alpha — P25963 (reviewed: P25963)

Alternative names: I-kappa-B-alpha, Major histocompatibility complex enhancer-binding protein MAD3

All UniProt accessions (7): P25963, A0A8V8TLC3, A0A8V8TLE7, G3V286, G3V2A2, G3V3I4, G3V3K1

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals. On cellular stimulation by immune and pro-inflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription.

Subunit / interactions. Interacts with RELA; the interaction requires the nuclear import signal. Part of a 70-90 kDa complex at least consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Interacts with NKIRAS1 and NKIRAS2. Interacts with isoform 1 and isoform 2 of RWDD3; the interaction enhances sumoylation. Interacts with PRMT2. Interacts with PRKACA in platelets; this interaction is disrupted by thrombin and collagen. Interacts with MEFV. Interacts with DDRGK1; positively regulates NFKBIA phosphorylation and degradation. Interacts with HNRNPA2B1; the interaction may be mediated by the RRM2 domain of HNRNPA2B1, and HNRNPA2B1 may interact simultaneously with FAM76B and either NFKBIA or NFKBIE to form a complex. (Microbial infection) Interacts with HBV protein X.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated at Ser-32 and Ser-36 by IKKA/CHUK and IKKB/IKBKB; disables inhibition of NF-kappa-B DNA-binding activity. Phosphorylation at positions 32 and 36 is prerequisite to recognition by the SCF(FBXW11) and SCF(BTRC) complexes, leading to polyubiquitination and subsequent degradation. Phosphorylated at Ser-32 in response to FK506 treatment: phosphorylation is independent of IKKA/CHUK and IKKB/IKBKB and promotes NFKBIA degradation, followed by NF-kappa-B activation. Phosphorylated at Tyr-42: its effect is however unclear. According to a report, phosphorylation at Tyr-42 activates NF-kappa-B without triggering proteolytic degradation of NFKBIA. According to another publication, phosphorylation at Tyr-42 inhibits NF-kappa-B activity by preventing phosphorylation at Ser-32 and Ser-36 and subsequent ubiquitination and degradation. Polyubiquitinated at Lys-21 and/or Lys-22 following phosphorylation at Ser-32 and Ser-36. Monoubiquitinated at Lys-21 and/or Lys-22 by UBE2D3. Ubiquitin chain elongation is then performed by CDC34 in cooperation with the SCF(FBXW11) E3 ligase complex, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. The resulting polyubiquitination leads to protein degradation. Also ubiquitinated by the SCF(BTRC) complex following stimulus-dependent phosphorylation at Ser-32 and Ser-36. Deubiquitinated by USP38, leading to NF-kappa-B inhibition. Sumoylated; sumoylation requires the presence of the nuclear import signal. Sumoylation blocks ubiquitination and proteasome-mediated degradation of the protein thereby increasing the protein stability. Hydroxylated by HIF1AN. (Microbial infection) Deubiquitinated by porcine reproductive and respiratory syndrome virus Nsp2 protein, which thereby interferes with NFKBIA degradation and impairs subsequent NF-kappa-B activation.

Disease relevance. Ectodermal dysplasia and immunodeficiency 2 (EDAID2) [MIM:612132] A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. This form of ectodermal dysplasia is associated with decreased production of pro-inflammatory cytokines and certain interferons, rendering patients susceptible to infection. EDAID2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Induction. Induced in adherent monocytes.

Similarity. Belongs to the NF-kappa-B inhibitor family.

RefSeq proteins (1): NP_065390* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR051070	NF-kappa-B_inhibitor	Family

Pfam: PF12796

UniProt features (67 total): mutagenesis site 21, helix 14, modified residue 10, repeat 5, turn 5, cross-link 3, short sequence motif 3, strand 2, chain 1, compositionally biased region 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6Y1J	X-RAY DIFFRACTION	1.13
9T9W	X-RAY DIFFRACTION	1.16
1IKN	X-RAY DIFFRACTION	2.3
1NFI	X-RAY DIFFRACTION	2.7
6TTU	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25963-F1	82.91	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 32, 36, 42, 210, 244, 283, 288, 291, 293, 299, 21, 21, 22

Mutagenesis-validated functional residues (21):

Position	Phenotype
21	little change in tax-stimulated transactivation. no sumoylation. greatly reduced tax- or cytokine-stimulated transactiva
22	little change in tax-stimulated transactivation. no sumoylation. greatly reduced tax- or cytokine-stimulated transactiva
31	loss of phosphorylation; when associated with a-35.
32	loss of phosphorylation, ubiquitination and degradation; when associated with a-36. abolished activation by fk506.
32	mimics phosphorylation; promoting ubiquitination and degradation; when associated with e-36.
32	decrease in phosphorylation and degradation; when associated with t-36.
35	loss in phosphorylation; when associated with a-31.
35	no change neither in phosphorylation, nor on degradation.
36	loss of phosphorylation, ubiquitination, and degradation; when associated with a-32. does not affect activation by fk506
36	mimics phosphorylation; promoting ubiquitination and degradation; when associated with e-32.
36	decrease in phosphorylation and degradation; when associated with t-32.
38	no change in tax-stimulated transactivation. no change in tax-stimulated transactivation; when associated with r-47.
42	no phosphorylation.
45–52	no nuclear export.
47	little change in tax-stimulated transactivation. no change in tax-stimulated transactivation; when associated with r-38.
115–120	greatly reduced nuclear localization. great reduction in its ability to inhibit dna binding of rela.
210	almost abolished ability to inhibit nf-kappa-b dna-binding activity; when associated with a-244.
234	no inducible ubiquitination nor protein degradation.
244	almost abolished ability to inhibit nf-kappa-b dna-binding activity; when associated with a-210.
262	no inducible ubiquitination nor protein degradation.
263	no inducible ubiquitination nor protein degradation.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-202424	Downstream TCR signaling
R-HSA-209560	NF-kB is activated and signals survival
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-4755510	SUMOylation of immune response proteins
R-HSA-5603029	IkBA variant leads to EDA-ID
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9020702	Interleukin-1 signaling
R-HSA-933542	TRAF6 mediated NF-kB activation
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9860927	Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells
R-HSA-9920951	Dengue virus modulates apoptosis

MSigDB gene sets: 920 (showing top): PID_BCR_5PATHWAY, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GSE45365_NK_CELL_VS_CD11B_DC_DN, BIOCARTA_TNFR2_PATHWAY, PID_HDAC_CLASSI_PATHWAY, CREL_01, BIOCARTA_RELA_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LIPID_STORAGE, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY

GO Biological Process (38): negative regulation of transcription by RNA polymerase II (GO:0000122), protein import into nucleus (GO:0006606), Notch signaling pathway (GO:0007219), canonical NF-kappaB signal transduction (GO:0007249), negative regulation of macrophage derived foam cell differentiation (GO:0010745), negative regulation of lipid storage (GO:0010888), lipopolysaccharide-mediated signaling pathway (GO:0031663), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of cholesterol transport (GO:0032375), response to muramyl dipeptide (GO:0032495), tumor necrosis factor-mediated signaling pathway (GO:0033209), toll-like receptor 4 signaling pathway (GO:0034142), response to muscle stretch (GO:0035994), non-canonical NF-kappaB signal transduction (GO:0038061), regulation of cell population proliferation (GO:0042127), negative regulation of protein import into nucleus (GO:0042308), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), response to exogenous dsRNA (GO:0043330), negative regulation of myeloid cell differentiation (GO:0045638), negative regulation of Notch signaling pathway (GO:0045746), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of inflammatory response (GO:0050729), B cell receptor signaling pathway (GO:0050853), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), cellular response to cold (GO:0070417), nucleotide-binding oligomerization domain containing 1 signaling pathway (GO:0070427), nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431), interleukin-1-mediated signaling pathway (GO:0070498), negative regulation of cytokine production involved in inflammatory response (GO:1900016), immune system process (GO:0002376), regulation of transcription by RNA polymerase II (GO:0006357), inflammatory response (GO:0006954), regulation of gene expression (GO:0010468), signal transduction involved in regulation of gene expression (GO:0023019), response to lipopolysaccharide (GO:0032496), positive regulation of DNA-templated transcription (GO:0045893), cellular response to cytokine stimulus (GO:0071345), cellular response to tumor necrosis factor (GO:0071356)

GO Molecular Function (9): nuclear localization sequence binding (GO:0008139), enzyme binding (GO:0019899), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), NF-kappaB binding (GO:0051059), protein sequestering activity (GO:0140311), molecular sequestering activity (GO:0140313), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), I-kappaB/NF-kappaB complex (GO:0033256)

Reactome top-level categories

Rollup of top-20 pathways:

Category	Pathways
Downstream signaling events of B Cell Receptor (BCR)	1
ZBP1(DAI) mediated induction of type I IFNs	1
TCR signaling	1
p75NTR signals via NF-kB	1
Fc epsilon receptor (FCERI) signaling	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
SUMO E3 ligases SUMOylate target proteins	1
Diseases associated with the TLR signaling cascade	1
C-type lectin receptors (CLRs)	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
cell surface receptor signaling pathway	2
intracellular signaling cassette	2
negative regulation of cell differentiation	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
macrophage derived foam cell differentiation	1
regulation of macrophage derived foam cell differentiation	1
regulation of lipid storage	1
lipid storage	1
negative regulation of cellular process	1
negative regulation of lipid localization	1
cellular response to lipopolysaccharide	1
cholesterol transport	1
negative regulation of sterol transport	1
regulation of cholesterol transport	1
response to nitrogen compound	1
response to oxygen-containing compound	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
cell surface toll-like receptor signaling pathway	1
response to mechanical stimulus	1
cell population proliferation	1
regulation of cellular process	1
protein import into nucleus	1
regulation of protein import into nucleus	1
negative regulation of nucleocytoplasmic transport	1
negative regulation of intracellular protein transport	1
negative regulation of protein localization to nucleus	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
response to dsRNA	1
myeloid cell differentiation	1

Protein interactions and networks

STRING

6036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFKBIA	RELA	Q04206	999
NFKBIA	REL	Q04864	999
NFKBIA	IKBKB	O14920	995
NFKBIA	NFKB1	P19838	986
NFKBIA	NFKBIB	Q15653	984
NFKBIA	BTRC	Q9Y297	984
NFKBIA	CHUK	O15111	973
NFKBIA	ARRB2	P32121	970
NFKBIA	RELB	Q01201	964
NFKBIA	TNF	P01375	937
NFKBIA	IKBKG	Q9Y6K9	936
NFKBIA	TRAF6	Q9Y4K3	934
NFKBIA	IL1B	P01584	927
NFKBIA	IL6	P05231	916
NFKBIA	STAT1	P42224	878

IntAct

265 interactions, top by confidence:

A	B	Type	Score
NFKBIA	RELA	psi-mi:“MI:0915”(physical association)	0.980
RELA	NFKBIA	psi-mi:“MI:0914”(association)	0.980
RELA	NFKBIA	psi-mi:“MI:0915”(physical association)	0.980
NFKBIA	RELA	psi-mi:“MI:0914”(association)	0.980
NFKBIA	RELA	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
IKBKB	NFKBIA	psi-mi:“MI:0217”(phosphorylation reaction)	0.970
NFKBIA	IKBKB	psi-mi:“MI:0217”(phosphorylation reaction)	0.970
NFKBIA	IKBKB	psi-mi:“MI:0407”(direct interaction)	0.970

BioGRID (690): NFKBIA (Biochemical Activity), NFKBIA (Biochemical Activity), NFKBIA (Biochemical Activity), NFKBIA (Co-purification), NFKBIA (Affinity Capture-Western), NFKBIA (Affinity Capture-Western), NFKBIA (Biochemical Activity), NFKBIA (Two-hybrid), NFKBIA (Biochemical Activity), NFKBIA (Biochemical Activity), NFKBIA (Biochemical Activity), NFKBIA (Biochemical Activity), NFKBIA (Affinity Capture-Western), BTRC (Affinity Capture-Western), NFKBIA (Biochemical Activity)

ESM2 similar proteins: A2APT9, A6NCL7, A7E3N7, O00221, O54910, O95153, O95382, P25963, P51617, Q08353, Q0P5G1, Q14154, Q15653, Q2TB02, Q3U0L2, Q3U5Q7, Q3UMR0, Q3UYR4, Q400C9, Q400G9, Q5RA67, Q5REW9, Q5T7N3, Q60778, Q63746, Q6P9J5, Q6PJG6, Q6ZVH7, Q6ZW76, Q7TNF8, Q7Z3H0, Q80UW5, Q8BH83, Q8BVF9, Q8BXP5, Q8CJ00, Q8NAG6, Q8NI38, Q8TE82, Q91974

Diamond homologs: A2AQH4, A6NGH8, P17369, P25799, P25963, Q2T9W8, Q4FE45, Q4JHE0, Q5H9F3, Q641X1, Q8BTI7, Q8NB46, Q96NS5, Q9CQ31, Q9CQM6, Q9H2K2, A2AS55, A6QR20, O04251, O75762, O90760, Q10311, Q1RJM6, Q24145, Q499M5, Q6RI86, Q70X92, Q86WC6, Q8BLA8, Q8N8A2, Q8R3P9, Q9BQI6, Q9J4Z4, Q9WV72, Q9Y575, Q9Z2F6, O00221, O54910, P19838, P20749

SIGNOR signaling

50 interactions.

A	Effect	B	Mechanism
RPS6KA2	down-regulates	NFKBIA	phosphorylation
IKBKE	“down-regulates quantity by destabilization”	NFKBIA	phosphorylation
NFKBIA	“down-regulates activity”	NFKB1	binding
NFKBIA	“up-regulates activity”	RELA	binding
IKK-complex	“down-regulates quantity by destabilization”	NFKBIA	phosphorylation
IKK-complex	down-regulates	NFKBIA	phosphorylation
NFKBIA	“down-regulates activity”	NfKb-p65/p50	binding
TBK1	“down-regulates quantity by destabilization”	NFKBIA	phosphorylation
PTPN13	“up-regulates quantity by stabilization”	NFKBIA	dephosphorylation
NFKBIA	“down-regulates quantity by repression”	S100A6	“transcriptional regulation”
NR3C1	“up-regulates quantity by expression”	NFKBIA	“transcriptional regulation”
G3BP2	“down-regulates activity”	NFKBIA	relocalization
ANXA3	“up-regulates activity”	NFKBIA
FBXW11	down-regulates	NFKBIA	ubiquitination
BPLF1	“down-regulates activity”	NFKBIA	deubiquitination
ZBTB20	“down-regulates quantity by repression”	NFKBIA	“transcriptional regulation”
UBE2E3	“up-regulates quantity by stabilization”	NFKBIA	sumoylation
RNF7	“down-regulates activity”	NFKBIA	ubiquitination
AURKC	“up-regulates activity”	NFKBIA	phosphorylation
AURKA	“down-regulates activity”	NFKBIA	phosphorylation
RPS6KA3	“down-regulates quantity by destabilization”	NFKBIA	phosphorylation
RPS6KA1	“up-regulates activity”	NFKBIA	phosphorylation
IKBKG	“down-regulates activity”	NFKBIA	phosphorylation
CSNK2A1	down-regulates	NFKBIA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RIP-mediated NFkB activation via ZBP1	7	81.1×	3e-10
MAP3K8 (TPL2)-dependent MAPK1/3 activation	6	73.8×	1e-08
TRAF6 mediated NF-kB activation	7	55.1×	4e-09
RHO GTPases activate IQGAPs	7	41.8×	2e-08
Gap junction trafficking and regulation	5	41.0×	4e-06
Gap junction trafficking	5	41.0×	4e-06
Activation of NF-kappaB in B cells	12	40.7×	5e-14
TAK1-dependent IKK and NF-kappa-B activation	7	36.3×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
non-canonical NF-kappaB signal transduction	6	80.2×	3e-08
canonical NF-kappaB signal transduction	8	46.5×	4e-09
mitotic cell cycle	5	10.6×	5e-03
microtubule cytoskeleton organization	5	9.6×	7e-03
positive regulation of canonical NF-kappaB signal transduction	6	6.9×	8e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	8	6.6×	2e-03
inflammatory response	10	6.0×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — DLBCLNOS, MLYM, NHL, PCM.

Clinical variants and AI predictions

ClinVar

341 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	143
Likely benign	127
Benign	39

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
14003	NM_020529.3(NFKBIA):c.95G>T (p.Ser32Ile)	Pathogenic
14005	NM_020529.3(NFKBIA):c.40G>T (p.Glu14Ter)	Pathogenic
2581077	NM_020529.3(NFKBIA):c.101T>C (p.Leu34Pro)	Pathogenic
280143	NM_020529.3(NFKBIA):c.25C>T (p.Gln9Ter)	Pathogenic
590308	NM_020529.3(NFKBIA):c.107C>A (p.Ser36Tyr)	Pathogenic
590309	NM_020529.3(NFKBIA):c.94A>G (p.Ser32Gly)	Pathogenic
590310	NM_020529.3(NFKBIA):c.96C>G (p.Ser32Arg)	Pathogenic
590311	NM_020529.3(NFKBIA):c.95G>A (p.Ser32Asn)	Pathogenic
3764637	NM_020529.3(NFKBIA):c.106T>G (p.Ser36Ala)	Likely pathogenic

SpliceAI

536 predictions. Top by Δscore:

Variant	Effect	Δscore
14:35402391:CA:C	donor_loss	1.0000
14:35402392:A:AC	donor_gain	1.0000
14:35402393:C:CC	donor_gain	1.0000
14:35402393:CCT:C	donor_gain	1.0000
14:35402659:GGCTC:G	acceptor_gain	1.0000
14:35402661:CTC:C	acceptor_gain	1.0000
14:35402662:TC:T	acceptor_gain	1.0000
14:35402663:CC:C	acceptor_gain	1.0000
14:35402664:C:CA	acceptor_loss	1.0000
14:35402664:C:CC	acceptor_gain	1.0000
14:35402671:C:CT	acceptor_gain	1.0000
14:35402671:C:T	acceptor_gain	1.0000
14:35402856:TGGC:T	acceptor_gain	1.0000
14:35402858:GCCTG:G	acceptor_loss	1.0000
14:35402860:C:CA	acceptor_loss	1.0000
14:35402860:C:CC	acceptor_gain	1.0000
14:35402861:T:A	acceptor_loss	1.0000
14:35403147:TAC:T	donor_loss	1.0000
14:35403148:A:AC	donor_gain	1.0000
14:35403148:A:AT	donor_loss	1.0000
14:35403148:AC:A	donor_gain	1.0000
14:35403149:C:CT	donor_gain	1.0000
14:35403149:CC:C	donor_gain	1.0000
14:35403149:CCA:C	donor_gain	1.0000
14:35403356:GGAGT:G	acceptor_gain	1.0000
14:35403357:GAGT:G	acceptor_gain	1.0000
14:35403358:AGT:A	acceptor_gain	1.0000
14:35403359:GT:G	acceptor_gain	1.0000
14:35403361:C:CC	acceptor_gain	1.0000
14:35403364:CGAA:C	acceptor_gain	1.0000

AlphaMissense

2064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:35402542:G:T	P253H	0.999
14:35402533:A:G	L256P	0.998
14:35402593:A:G	L236P	0.998
14:35402632:A:G	L223P	0.998
14:35402638:A:T	L221H	0.998
14:35402647:C:G	R218P	0.998
14:35403243:A:G	C152R	0.998
14:35403703:T:A	N108I	0.998
14:35402542:G:C	P253R	0.997
14:35402629:G:T	A224E	0.997
14:35402630:C:G	A224P	0.997
14:35402838:G:T	A190D	0.997
14:35403157:G:C	N180K	0.997
14:35403157:G:T	N180K	0.997
14:35403241:A:C	C152W	0.997
14:35403242:C:T	C152Y	0.997
14:35403345:C:G	A118P	0.997
14:35403702:G:C	N108K	0.997
14:35403702:G:T	N108K	0.997
14:35402635:T:C	H222R	0.996
14:35402638:A:G	L221P	0.996
14:35402641:G:T	A220D	0.996
14:35402650:C:A	G217V	0.996
14:35402851:A:G	C186R	0.996
14:35403275:T:A	D141V	0.996
14:35403276:C:G	D141H	0.996
14:35402802:A:G	L202S	0.995
14:35402849:A:C	C186W	0.995
14:35403158:T:A	N180I	0.995
14:35403266:C:A	G144V	0.995

dbSNP variants (sampled 300 via entrez): RS1000101668 (14:35405961 A>C), RS1001126070 (14:35401085 A>G), RS1001321553 (14:35406460 C>T), RS1001878800 (14:35401287 A>T), RS1002767172 (14:35406064 T>A), RS1002799784 (14:35402150 T>C), RS1003119861 (14:35402325 T>C), RS1003151098 (14:35403428 C>T), RS1003430593 (14:35405613 A>C,G), RS1003457252 (14:35403579 T>C,G), RS1004037904 (14:35405284 G>A), RS1004070372 (14:35405146 G>T), RS1004559040 (14:35401307 A>G), RS1005737490 (14:35403438 C>T), RS1007063154 (14:35401568 A>G)

Disease associations

OMIM: gene MIM:164008 | disease phenotypes: MIM:612132, MIM:612852

GenCC curated gene-disease

Disease	Classification	Inheritance
ectodermal dysplasia and immunodeficiency 2	Definitive	Autosomal dominant
ectodermal dysplasia and immune deficiency	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ectodermal dysplasia and immunodeficiency 2	Definitive	AD

Mondo (4): ectodermal dysplasia and immunodeficiency 2 (MONDO:0012806), prostate cancer (MONDO:0008315), sterile multifocal osteomyelitis with periostitis and pustulosis (MONDO:0013021), ectodermal dysplasia and immune deficiency (MONDO:0010293)

Orphanet (4): Hypohidrotic ectodermal dysplasia (Orphanet:238468), Hypohidrotic ectodermal dysplasia with immunodeficiency (Orphanet:98813), Familial prostate cancer (Orphanet:1331), Sterile multifocal osteomyelitis with periostitis and pustulosis (Orphanet:210115)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000403	Recurrent otitis media
HP:0000668	Hypodontia
HP:0000698	Conical tooth
HP:0000938	Osteopenia
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0000966	Hypohidrosis
HP:0000968	Ectodermal dysplasia
HP:0000970	Anhidrosis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001744	Splenomegaly
HP:0002007	Frontal bossing
HP:0002028	Chronic diarrhea
HP:0002037	Inflammation of the large intestine
HP:0002046	Heat intolerance
HP:0002205	Recurrent respiratory infections
HP:0002209	Sparse scalp hair
HP:0002240	Hepatomegaly
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002728	Chronic mucocutaneous candidiasis
HP:0002850	Decreased circulating total IgM
HP:0002960	Autoimmunity
HP:0003212	Increased circulating IgE concentration
HP:0003237	Increased circulating IgG concentration
HP:0003496	Increased circulating IgM level
HP:0003593	Infantile onset
HP:0004313	Decreased circulating immunoglobulin concentration

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST000833_13	Psoriasis	2.000000e-11
GCST000834_5	Psoriasis	2.000000e-08
GCST002738_3	Psoriasis	4.000000e-09
GCST002740_69	Inflammatory skin disease	9.000000e-09
GCST002874_10	Psoriasis	2.000000e-10
GCST002874_49	Psoriasis	3.000000e-06
GCST002874_51	Psoriasis	5.000000e-06
GCST003268_15	Psoriasis vulgaris	3.000000e-11
GCST004067_201	Hip circumference adjusted for BMI	3.000000e-09
GCST004067_54	Hip circumference adjusted for BMI	5.000000e-11
GCST004627_153	Lymphocyte count	5.000000e-13
GCST004776_2	Systolic blood pressure	7.000000e-07
GCST004776_73	Systolic blood pressure	1.000000e-12
GCST005527_16	Psoriasis	3.000000e-17
GCST005537_116	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	3.000000e-10
GCST005537_118	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	3.000000e-07
GCST006014_22	Creatine kinase levels	3.000000e-11
GCST007096_67	Pulse pressure	2.000000e-10
GCST007099_47	Systolic blood pressure	4.000000e-11
GCST007267_139	Systolic blood pressure	2.000000e-10
GCST007269_326	Pulse pressure	5.000000e-12
GCST007798_138	Asthma	1.000000e-09
GCST007800_83	Asthma (childhood onset)	4.000000e-07
GCST008479_34	Psoriasis	1.000000e-08
GCST009718_10	Eczema	3.000000e-09
GCST010042_10	Asthma	7.000000e-11
GCST010043_66	Asthma	6.000000e-11
GCST010320_21	PR interval	2.000000e-10
GCST010321_85	PR interval	2.000000e-09
GCST011389_18	Rheumatoid arthritis	5.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris
EFO:0008039	BMI-adjusted hip circumference
EFO:0004587	lymphocyte count
EFO:0006335	systolic blood pressure
EFO:0004534	creatine kinase measurement
EFO:0005763	pulse pressure measurement
EFO:0004462	PR interval
EFO:0004980	appendicular lean mass

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C557815	Deficiency of interleukin-1 receptor antagonist (supp.)
C567411	Ectodermal Dysplasia, Anhidrotic, With T-Cell Immunodeficiency, Autosomal Dominant (supp.)
C536181	Ectodermal dysplasia, hypohidrotic, with immune deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2898 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

5 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2233406	Toxicity	3	gefitinib	Diarrhea;Non-Small Cell Lung Carcinoma
rs2233407	Toxicity	3	gefitinib	Non-Small Cell Lung Carcinoma;Toxic liver disease
rs2233409	Toxicity	3	gefitinib	Diarrhea;Non-Small Cell Lung Carcinoma
rs696	Dosage	3	sufentanil	Pain;Postoperative
rs8904	Toxicity	3	gefitinib	Exanthema;Non-Small Cell Lung Carcinoma

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs696	NFKBIA	3	1.75	1	sufentanil
rs2233406	NFKBIA	3	2.00	1	gefitinib
rs2233407	NFKBIA	3	2.00	1	gefitinib
rs2233409	NFKBIA	3	2.50	1	gefitinib
rs8904	NFKBIA	3	2.00	1	gefitinib

Binding affinities (BindingDB)

1 measured of 4 human assays (4 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
25-HYDROXY PHYSALIN F	IC50	30100 nM

ChEMBL bioactivities

54 potent at pChembl≥5 of 72 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	EC50	500	nM	CHEMBL271669
6.16	EC50	700	nM	CHEMBL272552
6.13	Kd	741	nM	CHEMBL4071045
6.10	EC50	800	nM	CHEMBL271669
6.05	EC50	900	nM	BI-605906
6.00	EC50	1000	nM	MG-132
6.00	EC50	1000	nM	CHEMBL429586
6.00	EC50	1000	nM	CHEMBL272552
5.96	EC50	1100	nM	CHEMBL429599
5.89	EC50	1300	nM	CHEMBL404128
5.89	EC50	1300	nM	CHEMBL272553
5.85	EC50	1400	nM	CHEMBL273149
5.85	EC50	1400	nM	CHEMBL256403
5.85	EC50	1400	nM	CHEMBL404128
5.80	EC50	1600	nM	CHEMBL272553
5.68	EC50	2100	nM	CHEMBL256403
5.66	EC50	2200	nM	CHEMBL428064
5.64	EC50	2300	nM	CHEMBL273149
5.58	EC50	2600	nM	CHEMBL428064
5.57	EC50	2700	nM	CHEMBL257446
5.52	EC50	3000	nM	CHEMBL401505
5.47	EC50	3400	nM	CHEMBL273147
5.44	EC50	3600	nM	CHEMBL404588
5.44	EC50	3600	nM	CHEMBL269941
5.43	EC50	3700	nM	CHEMBL273147
5.40	EC50	4000	nM	CHEMBL256061
5.39	EC50	4100	nM	CHEMBL270799
5.28	EC50	5200	nM	MG-132
5.28	EC50	5300	nM	CHEMBL257234
5.23	EC50	5900	nM	CHEMBL401504
5.22	EC50	6000	nM	CHEMBL402638
5.21	EC50	6100	nM	CHEMBL256609
5.19	EC50	6500	nM	CHEMBL540966
5.19	EC50	6400	nM	CHEMBL256609
5.17	EC50	6800	nM	CHEMBL269942
5.17	EC50	6800	nM	CHEMBL256042
5.17	EC50	6800	nM	CHEMBL256204
5.17	EC50	6800	nM	CHEMBL401504
5.16	EC50	7000	nM	CHEMBL270798
5.14	EC50	7200	nM	CHEMBL273148
5.12	EC50	7600	nM	CHEMBL269942
5.10	EC50	8000	nM	CHEMBL403333
5.10	EC50	8000	nM	CHEMBL258314
5.10	EC50	8000	nM	CHEMBL256204
5.07	EC50	8500	nM	CHEMBL256062
5.05	EC50	8900	nM	CHEMBL273148
5.05	EC50	9000	nM	CHEMBL257234
5.03	EC50	9400	nM	CHEMBL401505
5.00	EC50	1e+04	nM	CHEMBL269941
5.00	EC50	1e+04	nM	CHEMBL270798

PubChem BioAssay actives

53 with measured affinity, of 188 total; 31 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
9-methyl-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	0.5000	uM
9-(trifluoromethyl)-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	0.7000	uM
5-[[(5S)-6-amino-5-[[2-[(4S,10S,16S,22S)-12-[2-(1,3-benzodioxol-5-yl)acetyl]-4,22-dibenzyl-10,16-bis(2-carboxyethyl)-18-(3-carboxypropanoyl)-6-(3-cyclohexylpropanoyl)-2,8,14,20,25-pentaoxo-28-thia-3,6,9,12,15,18,21,24-octazabicyclo[28.2.2]tetratriaconta-1(32),30,33-trien-24-yl]acetyl]amino]-6-oxohexyl]carbamothioylamino]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1471866: Binding affinity to NFKBIA (unknown origin)	kd	0.7410	uM
benzyl N-[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]carbamate	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.0000	uM
2-methyl-5-nitro-N-quinolin-8-ylbenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.0000	uM
9-chloro-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.1000	uM
9-methoxy-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.3000	uM
11-methoxy-9-methyl-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.3000	uM
11-methoxy-3,9-dimethyl-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.4000	uM
5-chloro-N-(2-methylquinolin-8-yl)thiophene-2-sulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	1.4000	uM
5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	2.2000	uM
5-chloro-N-quinolin-8-ylthiophene-2-sulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	2.7000	uM
2-amino-N-(6-methoxy-2-methylquinolin-8-yl)-4-methylbenzenesulfonamide	317145: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells assessed as ratio of green light emiting IkappaBalpha-fused luciferase expression to red light emiting native luciferase expression	ec50	3.0000	uM
9-methoxy-3-methyl-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317145: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells assessed as ratio of green light emiting IkappaBalpha-fused luciferase expression to red light emiting native luciferase expression	ec50	3.4000	uM
N-(2-methylquinolin-8-yl)-2-nitro-4-(trifluoromethyl)benzenesulfonamide	317145: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells assessed as ratio of green light emiting IkappaBalpha-fused luciferase expression to red light emiting native luciferase expression	ec50	3.6000	uM
2-nitro-N-quinolin-8-yl-4-(trifluoromethyl)benzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	3.6000	uM
2-amino-N-(6-methoxyquinolin-8-yl)-4-methylbenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	4.0000	uM
9-fluoro-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	4.1000	uM
N-quinolin-8-ylthiophene-2-sulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	5.3000	uM
5-bromo-N-quinolin-8-ylthiophene-2-sulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	5.9000	uM
N-(2-methylquinolin-8-yl)-3-nitrobenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	6.0000	uM
5-bromo-N-(2-methylquinolin-8-yl)thiophene-2-sulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	6.1000	uM
4-nitro-N-quinolin-8-ylbenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	6.5000	uM
N-(2-methylquinolin-8-yl)-2-nitrobenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	6.8000	uM
N-(6-methoxyquinolin-8-yl)-4-methyl-2-nitrobenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	6.8000	uM
4-methyl-2-nitro-N-quinolin-8-ylbenzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	6.8000	uM
2-methyl-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	7.0000	uM
3-methyl-9-(trifluoromethyl)-5H-quinolino[8,7-c][1,2]benzothiazine 6,6-dioxide	317145: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells assessed as ratio of green light emiting IkappaBalpha-fused luciferase expression to red light emiting native luciferase expression	ec50	7.2000	uM
2-amino-N-(2-methylquinolin-8-yl)benzenesulfonamide	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	8.0000	uM
3-methyl-6,6-dioxo-5H-quinolino[8,7-c][1,2]benzothiazin-9-ol	317143: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells by green light emiting IkappaBalpha-fused luciferase reporter gene assay	ec50	8.0000	uM
2-amino-N-quinolin-8-ylbenzenesulfonamide	317145: Induction of human IkappaBalpha stabilization in OCI-Ly3 cells assessed as ratio of green light emiting IkappaBalpha-fused luciferase expression to red light emiting native luciferase expression	ec50	8.5000	uM

CTD chemical–gene interactions

564 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	increases localization, affects reaction, affects cotreatment, affects localization, affects expression (+10 more)	55
Tetradecanoylphorbol Acetate	decreases phosphorylation, increases expression, decreases reaction, increases degradation, affects cotreatment (+7 more)	34
sodium arsenite	increases expression, increases phosphorylation, affects expression, affects cotreatment, decreases degradation (+6 more)	18
Resveratrol	decreases degradation, decreases phosphorylation, affects localization, increases phosphorylation, increases expression (+5 more)	18
Curcumin	increases phosphorylation, increases expression, decreases expression, increases degradation, decreases phosphorylation (+2 more)	17
Arsenic Trioxide	affects cotreatment, decreases degradation, increases degradation, increases phosphorylation, decreases phosphorylation (+7 more)	16
Quercetin	affects cotreatment, decreases degradation, decreases phosphorylation, decreases reaction, increases degradation (+4 more)	15
Hydrogen Peroxide	increases activity, increases expression, decreases reaction, increases phosphorylation, affects expression (+4 more)	12
Dexamethasone	affects cotreatment, decreases reaction, increases phosphorylation, increases expression, increases reaction (+1 more)	11
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression, affects binding, increases degradation, decreases phosphorylation, decreases reaction (+3 more)	10
Aspirin	decreases expression, decreases phosphorylation, increases expression, decreases reaction, increases phosphorylation (+1 more)	10
Tobacco Smoke Pollution	decreases reaction, increases degradation, increases expression, decreases expression, affects expression (+1 more)	10
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects cotreatment, increases expression, decreases reaction, decreases degradation, increases reaction (+5 more)	9
Bortezomib	increases degradation, increases reaction, affects cotreatment, affects expression, decreases degradation (+5 more)	9
Calcimycin	affects cotreatment, increases degradation, decreases reaction, increases phosphorylation	8
Acetylcysteine	decreases phosphorylation, decreases reaction, increases expression, increases phosphorylation, increases degradation (+3 more)	7
Doxorubicin	affects degradation, decreases reaction, decreases expression, increases degradation, increases phosphorylation (+3 more)	7
Estradiol	affects expression, decreases reaction, increases degradation, increases phosphorylation, increases reaction (+1 more)	7
nickel chloride	decreases reaction, increases phosphorylation, decreases expression, increases expression	6
Fluorouracil	decreases expression, decreases reaction, affects activity, increases expression, increases phosphorylation (+3 more)	6
Asbestos, Crocidolite	increases expression, decreases reaction, affects expression, decreases expression, increases phosphorylation	6
Cadmium Chloride	increases expression, decreases reaction, increases phosphorylation, decreases expression, increases abundance (+2 more)	6
Particulate Matter	increases expression, increases degradation, decreases expression, decreases reaction, increases phosphorylation (+2 more)	6
bisphenol A	increases phosphorylation, increases expression, decreases reaction, affects cotreatment, affects expression (+2 more)	5
Air Pollutants	affects expression, decreases expression, increases expression, affects cotreatment, increases abundance	5
Cycloheximide	affects reaction, decreases reaction, increases expression, decreases expression, increases reaction (+1 more)	5
arsenite	increases phosphorylation, affects degradation, decreases reaction, increases degradation, decreases phosphorylation	4
nickel sulfate	decreases reaction, increases degradation, increases activity, increases expression	4
diallyl trisulfide	increases expression, increases phosphorylation, decreases degradation, decreases phosphorylation	4
chrysin	increases phosphorylation, decreases expression, affects cotreatment, decreases reaction, increases degradation	4

ChEMBL screening assays

48 unique, capped per target: 48 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1057324	Binding	Inhibition of TNF-alpha-stimulated IkappaBalpha degradation in human A549 cells at 0.1 to 100 uM preincubated for 1 hr before TNFalpha challenge measured after 10 mins by Western blot analysis	Peperomins as anti-inflammatory agents that inhibit the NF-kappaB signaling pathway. — Bioorg Med Chem Lett

Cellosaurus cell lines

17 cell lines: 13 cancer cell line, 4 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D2KR	Abcam Raji NFKBIA KO	Cancer cell line	Male
CVCL_D7VT	Ubigene A-549 NFKBIA KO	Cancer cell line	Male
CVCL_D8RA	Ubigene HCT 116 NFKBIA KO	Cancer cell line	Male
CVCL_D9LA	Ubigene HEK293 NFKBIA KO	Transformed cell line	Female
CVCL_E0J3	Ubigene HeLa NFKBIA KO	Cancer cell line	Female
CVCL_KW16	PathHunter A549 IkappaB Degradation	Cancer cell line	Male
CVCL_KZ58	PathHunter HEK 293 IkappaB Degradation	Transformed cell line	Female
CVCL_KZ65	PathHunter HEK 293 RELA-IkappaB Nuclear Translocation	Transformed cell line	Female
CVCL_KZ68	PathHunter Jurkat IkappaB Degradation	Cancer cell line	Male
CVCL_KZ70	PathHunter THP-1 IkappaB Degradation	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer