NCF2

Summary

NCF2 (neutrophil cytosolic factor 2, HGNC:7661) is a protein-coding gene on chromosome 1q25.3, encoding Neutrophil cytosol factor 2 (P19878). Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)).

This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 4688 — RefSeq curated summary.

At a glance

• Gene–disease (curated): granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 678 total — 48 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 57
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7661
Approved symbol	NCF2
Name	neutrophil cytosolic factor 2
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	p67phox, NOXA2
Ensembl gene	ENSG00000116701
Ensembl biotype	protein_coding
OMIM	608515
Entrez	4688

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000367535, ENST00000367536, ENST00000413720, ENST00000418089, ENST00000419402, ENST00000420553, ENST00000469280, ENST00000697329, ENST00000697330, ENST00000697351, ENST00000697352, ENST00000697353, ENST00000873217, ENST00000873218, ENST00000946289, ENST00000946290, ENST00000946291, ENST00000946292, ENST00000946293, ENST00000946294, ENST00000946295

RefSeq mRNA: 5 — MANE Select: NM_000433 NM_000433, NM_001127651, NM_001190789, NM_001190794, NM_001410895

CCDS: CCDS1356, CCDS53446, CCDS53447, CCDS91125

Canonical transcript exons

ENST00000367535 — 15 exons

Exon	Start	End
ENSE00000774250	183586895	183586977
ENSE00000922162	183574487	183574621
ENSE00001813568	183555562	183556230
ENSE00001896738	183590156	183590459
ENSE00003970286	183573185	183573292
ENSE00003970288	183577599	183577707
ENSE00003970291	183565704	183565779
ENSE00003970292	183566920	183566988
ENSE00003970293	183570780	183570839
ENSE00003970294	183563195	183563306
ENSE00003970295	183567204	183567345
ENSE00003970296	183560096	183560273
ENSE00003970297	183563434	183563585
ENSE00003970298	183569142	183569185
ENSE00003970300	183564005	183564030

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.48.

FANTOM5 (CAGE): breadth broad, TPM avg 44.3945 / max 2814.1513, expressed in 711 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16220	31.0808	476
16221	3.4605	306
16222	2.0884	266
16230	1.9958	225
16225	1.2246	218
16223	1.1875	213
16224	1.0515	240
16229	0.8107	190
16213	0.5515	135
16219	0.3389	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.48	gold quality
mononuclear cell	CL:0000842	99.45	gold quality
leukocyte	CL:0000738	99.43	gold quality
blood	UBERON:0000178	99.35	gold quality
granulocyte	CL:0000094	99.02	gold quality
bone marrow	UBERON:0002371	97.51	gold quality
bone marrow cell	CL:0002092	96.54	gold quality
right lung	UBERON:0002167	96.13	gold quality
spleen	UBERON:0002106	95.26	gold quality
trabecular bone tissue	UBERON:0002483	94.78	gold quality
upper lobe of left lung	UBERON:0008952	94.69	gold quality
periodontal ligament	UBERON:0008266	94.66	gold quality
upper lobe of lung	UBERON:0008948	94.18	gold quality
lung	UBERON:0002048	90.74	gold quality
vermiform appendix	UBERON:0001154	89.41	gold quality
lower lobe of lung	UBERON:0008949	89.38	gold quality
gall bladder	UBERON:0002110	89.19	gold quality
visceral pleura	UBERON:0002401	86.80	gold quality
omental fat pad	UBERON:0010414	85.39	gold quality
peritoneum	UBERON:0002358	85.27	gold quality
right coronary artery	UBERON:0001625	85.01	gold quality
amniotic fluid	UBERON:0000173	84.94	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.78	silver quality
bronchial epithelial cell	CL:0002328	83.48	gold quality
skin of leg	UBERON:0001511	82.96	gold quality
skin of abdomen	UBERON:0001416	82.60	gold quality
islet of Langerhans	UBERON:0000006	82.48	gold quality
palpebral conjunctiva	UBERON:0001812	82.35	gold quality
epithelium of bronchus	UBERON:0002031	82.35	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	76.91
E-CURD-122	yes	70.93
E-MTAB-6701	yes	30.88
E-CURD-112	yes	29.22
E-MTAB-6678	yes	28.23
E-MTAB-9221	yes	27.35
E-GEOD-130148	yes	23.01
E-MTAB-9067	yes	14.96
E-MTAB-8498	yes	10.05
E-MTAB-9801	yes	8.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, HOXA10, IRF1, IRF8, MED15, PLAGL2, SPI1, TP53, ZNF354C

miRNA regulators (miRDB)

20 targeting NCF2, 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-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-532-5P	98.43	67.53	760
HSA-MIR-218-2-3P	98.08	67.21	601
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-4797-3P	97.48	67.14	989
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-4633-5P	96.17	66.36	501

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Transcriptional regulation of the p67phox gene: role of AP-1 in concert with myeloid-specific transcription factors. Identification of cis-regulatory elements regulating p67(phox), with identification of specific sequences of TF binding sites. (PMID:11483614)
• In a cell-free system, covalent binding between C-terminal-truncated p67phox and rac in the correct fusion order produces a more stable complex than the individual components and significantly influences the duration of fusion-produced oxidase activation. (PMID:11705402)
• detailed study of the protein-protein interactions that occur in the p40-p47-p67(phox) complex of the resting oxidase (PMID:11796733)
• p22(phox), gp91(phox), p47(phox), p67(phox), and p40(phox) existed as a functional complex in the cytoskeletal fraction. (PMID:11893732)
• Val204 in p67(phox), previously shown to be required for NADPH oxidase activity under cell-free conditions, was found to be essential for superoxide production by intact COS-phox cells. (PMID:11929750)
• effect of cPLA2 on its translocation (PMID:12101222)
• NAD(P)H oxidase subunits p47(phox) and p67(phox) are expressed in platelets; and NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment. (PMID:12130503)
• p67phox and p47phox have roles in regulating a change of conformation in cytochrome b558, which initiates the electron transfer in NADPH oxidase activation (PMID:12719414)
• NOXO1, p47phox, and p67phox regulate Nox3 (PMID:15181005)
• NAD(P)H oxidase activity is associated with increased protein levels of p22phox, p47phox, and p67phox, and increased p22phox and nox2 (gp91phox) mRNA expression. (PMID:15256399)
• Increased expression and activity of NAD(P)H oxidase subunits and xanthine oxidase, in part mediated through angiotensin II and PKC-dependent pathways, are important mechanisms underlying increased oxidative stress in human coronary artery disease (PMID:16293794)
• Here we show that the p47(phox)-p67(phox) interaction is disrupted not only by deletion of the PRR but also by substitution for basic residues in the extra-PRR (K383E/K385E). (PMID:16297854)
• Expression of p67(phox) is regulated through mechanisms that include modulation of transcription and translation. (PMID:16310324)
• These results indicate that Hcy (homocysteine)-stimulated superoxide anion production in monocytes is regulated through PKC-dependent phosphorylation of p47phox and p67phox subunits of NADPH oxidase. (PMID:16626305)
• NADPH oxidase assembly from p67phox was studies at the single-cell level. (PMID:16987007)
• chemoattractant-stimulated superoxide production can be amplified by a positive feedback loop in which p67(phox) targets Vav1-mediated Rac activation (PMID:17060455)
• These data clearly identify PLAGL2 as a novel regulator of NCF2/p67phox gene expression as well as NADPH oxidase activity and contribute to a greater understanding of the transcriptional regulation of NCF2. (PMID:17462995)
• There is an increased expression of NADPH oxidase p47(-PHOX) and p67(-PHOX) factor in idiopathic pulmonary fibrosis patients. (PMID:17651608)
• a novel single nucleotide polymorphism in the promoter region (PMID:17712795)
• Single nucleotide polymorphism leads to alternative splicing without altering gene expression or respiratory burst activity. (PMID:17910042)
• p40(phox) translocates p67(phox) to the region of the cytochrome and subsequently switches the oxidase to an activated state dependent upon PtdIns(3)P and SH3 domain engagement. (PMID:18029359)
• As(2)O(3) induced phosphorylation and membrane translocation of the NADPH oxidase subunit p47(phox) and it also increased translocation of Rac1 and p67(phox). (PMID:18424721)
• mutations in CYBB, NCF1, CYBA or NCF2 may play a role in chronic granulomatous disease (PMID:18546332)
• autosomal recessive CGD due to NCF-2 gene mutations, and a novel homozygous and hypomorphic NCF-2 gene mutation was found. (PMID:18625437)
• p67(phox)-SH3(N) specifically functions in gp91(phox)/Nox2 activation probably via facilitating oxidase assembly. (PMID:19116138)
• Nine SNPs distributed across eight genetic regions (ALOX5, IRAK3, ITGB2, NCF2, NFKB1, SELP, SOD1, and STAT1) were associated with risk of glioma with P value of <0.01. (PMID:19423540)
• involved in insulin-stimulated O(2)(-) production in monocytes (PMID:19439231)
• Conclude that acute exercise increases intracellular NO in endothelial progenitor cells through an NADPH oxidase-inhibition mechanism in sedentary men. (PMID:19717732)
• Alu-induced deletion of the TPR4 domain of p67-phox leads to loss of function and accelerated degradation of the protein. (PMID:19953534)
• These findings identify the activation of PKC delta and NADPH oxidase as crucial steps in retinoic acid-induced neuroblastoma cell differentiation. (PMID:20074641)
• All mutations and some polymorphisms identified in the NCF2 gene in the autosomal forms of chronic granulomatous disease are listed. Review. (PMID:20167518)
• Here we show that p67(phox)adopts an elongated conformation when it exists not only as a monomer but also as the heterotrimer (PMID:20375610)
• the extended activation domain of p67(phox) (amino acids 190-210) containing the D(Y/F)LGK motif plays an essential role in oxidase activation probably by interacting with gp91(phox). (PMID:20679349)
• The genetic variation in the NCF2 gene was found to associate with SLE in US and European populations (PMID:20842512)
• High NCF2 expression in the cytoplasm is associated with uterine cervix carcinogenesis. (PMID:21119665)
• This variant reduced binding of the NCF2 gene product p67(phox) to RAC2. This study found a novel genetic association of RAC2 with Crohn’s disease (CD) and replicated the previously reported association of NCF4 with ileal CD. (PMID:21900546)
• p67(phox) has a critical role to support for reactive oxygen species production on the level of individual phagosomes. (PMID:21954286)
• Association analysis identified five SLE susceptibility genes reaching genome-wide levels of significance : NCF2 ,IKZF1 ,IRF8 ,IFIH1 , and TYK2 (PMID:22046141)
• NCF2 is strongly associated with increased risk of childhood- and adult-onset systemic lupus erythematosus through a single nonsynonymous coding mutation (H389Q) in exon 12. (PMID:22203994)
• Eight novel mutations in CYBB and NCF2 genes were identified in patients with chronic granulomatous disease. (PMID:22562447)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncf2	ENSDARG00000005821
mus_musculus	Ncf2	ENSMUSG00000026480
rattus_norvegicus	Ncf2	ENSRNOG00000028016

Paralogs (1): NOXA1 (ENSG00000188747)

Protein

Protein identifiers

Neutrophil cytosol factor 2 — P19878 (reviewed: P19878)

Alternative names: 67 kDa neutrophil oxidase factor, NADPH oxidase activator 2, Neutrophil NADPH oxidase factor 2, p67-phox

All UniProt accessions (3): P19878, A0A0S2Z457, A0A8V8TMB9

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)). In the activated complex, electrons are first transferred from NADPH to flavin adenine dinucleotide (FAD) and subsequently transferred via two heme molecules to molecular oxygen, producing superoxide through an outer-sphere reaction. Activation of the NADPH oxidase complex is initiated by the assembly of cytosolic subunits of the NADPH oxidase complex with the core NADPH oxidase complex to form a complex at the plasma membrane or phagosomal membrane. This activation process is initiated by phosphorylation dependent binding of the cytosolic NCF1/p47-phox subunit to the C-terminus of CYBA/p22-phox.

Subunit / interactions. Component of the phagocyte NADPH oxidase complex composed of an obligatory core heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic regulatory subunits NCF1/p47-phox, NCF2/p67-phox, NCF4/p40-phox and the small GTPase RAC1 or RAC2. Part of a cytosolic complex composed at least by NCF1, NCF2 and NCF4. Interacts with NCF4. Interacts (via the C-terminal SH3 domain) with NCF1 (via C-terminus). Interacts with SYTL1 and RAC1. May interact with NOXO1. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with GBP7 (via GB1/RHD3-type G domain). Interacts with CYBB; the interaction is enhanced in the presence of GBP7.

Subcellular location. Cytoplasm.

Disease relevance. Granulomatous disease, chronic, autosomal recessive, 2 (CGD2) [MIM:233710] A form of chronic granulomatous disease, a primary immunodeficiency characterized by severe recurrent bacterial and fungal infections, along with manifestations of chronic granulomatous inflammation. It results from an impaired ability of phagocytes to mount a burst of reactive oxygen species in response to pathogens. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The OPR/PB1 domain mediates the association with NCF4/p40-PHOX.

Similarity. Belongs to the NCF2/NOXA1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
P19878-1	1	yes
P19878-2	2
P19878-3	3
P19878-4	4

RefSeq proteins (5): NP_000424, NP_001121123, NP_001177718, NP_001177723, NP_001397824 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000270	PB1_dom	Domain
IPR001452	SH3_domain	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR034885	PB1_P67	Domain
IPR034889	NCF2_SH3	Domain
IPR035546	p67phox_SH3_1	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051864	NCF2_NOXA1	Family
IPR053793	PB1-like	Domain

Pfam: PF00018, PF00564, PF13181

UniProt features (82 total): sequence variant 28, strand 19, helix 16, repeat 3, compositionally biased region 3, splice variant 3, domain 3, modified residue 2, turn 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1HH8	X-RAY DIFFRACTION	1.8
1WM5	X-RAY DIFFRACTION	1.95
1OEY	X-RAY DIFFRACTION	2
1E96	X-RAY DIFFRACTION	2.4
8WEJ	ELECTRON MICROSCOPY	2.79
1K4U	SOLUTION NMR
2DMO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19878-F1	78.99	0.44

Antibody-complex structures (SAbDab): 1 — 8WEJ

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 (2): 233, 399

Function

Pathways and Gene Ontology

Reactome pathways

23 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-1236973	Cross-presentation of particulate exogenous antigens (phagosomes)
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-1236975	Antigen processing-Cross presentation
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194138	Signaling by VEGF
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2262752	Cellular responses to stress
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 434 (showing top): MODULE_93, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, LU_IL4_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_SECRETORY_GRANULE, MODULE_45, MODULE_317, GOBP_SUPEROXIDE_METABOLIC_PROCESS, CROONQUIST_NRAS_SIGNALING_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING

GO Biological Process (6): superoxide metabolic process (GO:0006801), phagocytosis (GO:0006909), cellular defense response (GO:0006968), superoxide anion generation (GO:0042554), innate immune response (GO:0045087), respiratory burst (GO:0045730)

GO Molecular Function (5): electron transfer activity (GO:0009055), superoxide-generating NAD(P)H oxidase activity (GO:0016175), superoxide-generating NADPH oxidase activator activity (GO:0016176), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (7): acrosomal vesicle (GO:0001669), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), phagolysosome (GO:0032010), NADPH oxidase complex (GO:0043020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
RHO GTPase cycle	3
Immune System	2
Signaling by Rho GTPases	2
Innate Immune System	1
Antigen processing-Cross presentation	1
Cellular response to chemical stress	1
Signaling by VEGF	1
RHO GTPase Effectors	1
Class I MHC mediated antigen processing & presentation	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Cellular responses to stimuli	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
reactive oxygen species metabolic process	1
endocytosis	1
defense response	1
superoxide metabolic process	1
immune response	1
defense response to symbiont	1
metabolic process	1
molecular_function	1
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	1
enzyme activator activity	1
superoxide-generating NADPH oxidase activity	1
GTPase binding	1
binding	1
secretory granule	1
cytoplasm	1
membrane	1
cell periphery	1
secondary lysosome	1
phagocytic vesicle	1
plasma membrane protein complex	1
oxidoreductase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2012 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCF2	CYBA	P13498	999
NCF2	NCF1	P14598	999
NCF2	CYBB	P04839	999
NCF2	NOXO1	Q8NFA2	999
NCF2	RAC2	P15153	998
NCF2	NOX1	Q9Y5S8	998
NCF2	NOX4	Q9NPH5	996
NCF2	AKT1	P31749	993
NCF2	NCF4	Q15080	991
NCF2	NOXA1	Q86UR1	985
NCF2	RAC1	P15154	972
NCF2	NOX3	Q9HBY0	964
NCF2	DUOX1	Q9NRD9	955
NCF2	MT-CYB	P00156	951
NCF2	NOX5	Q96PH1	937

IntAct

78 interactions, top by confidence:

A	B	Type	Score
NCF2	KIFAP3	psi-mi:“MI:0915”(physical association)	0.930
KIFAP3	NCF2	psi-mi:“MI:0915”(physical association)	0.930
NCF1	NCF2	psi-mi:“MI:0915”(physical association)	0.930
NCF2	NCF1	psi-mi:“MI:0407”(direct interaction)	0.930
NCF1	NCF2	psi-mi:“MI:0407”(direct interaction)	0.930
NCF2	NCF1	psi-mi:“MI:0915”(physical association)	0.930
NCF2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.810
GOLGA2	NCF2	psi-mi:“MI:0915”(physical association)	0.810

BioGRID (78): NCF2 (Reconstituted Complex), NCF2 (Reconstituted Complex), RAC1 (Affinity Capture-Western), NCF2 (Two-hybrid), KIFAP3 (Two-hybrid), NCF2 (Two-hybrid), NCF2 (Affinity Capture-Western), PLA2G4A (Reconstituted Complex), NCF2 (Affinity Capture-Western), GOLGA2 (Two-hybrid), KIFAP3 (Two-hybrid), CAMSAP3 (Affinity Capture-MS), BPGM (Affinity Capture-MS), NCF2 (Affinity Capture-MS), USP47 (Affinity Capture-MS)

ESM2 similar proteins: A0AVI2, A0FGR9, A0JP70, A2AAJ9, A2ABU4, A2RUH7, A6QQP7, O01761, O14976, O15068, O70145, O70468, O75923, O77775, O88599, P0C5E3, P11799, P19878, P56741, P70402, P70600, P97874, Q05623, Q13203, Q14289, Q15746, Q29RQ5, Q3UMY5, Q5DTI8, Q5FW53, Q5PQM4, Q5RKG2, Q5VST9, Q5VTT5, Q62234, Q64096, Q6P7F1, Q7ZZC8, Q80W93, Q8C7M3

Diamond homologs: A1CEK6, A1DFN5, A1DFP5, A2QW93, A2QWA2, A3LXQ8, A4FU49, A4RF61, A6QLK6, B0BNA1, F4KAU9, O08641, O14964, O35179, O35180, O35413, O35964, O43125, O74749, O80910, O94875, P07751, P0CR78, P0CR79, P10569, P19878, P29355, P38753, P62993, P62994, P87379, Q06449, Q07883, Q08012, Q0CJU8, Q0CJV3, Q0U4Z8, Q0U6X7, Q0V8S0, Q15080

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IRF8	“up-regulates quantity by expression”	NCF2	“transcriptional regulation”
NCF2	“form complex”	“Phagocyte NADPH oxidase complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
RHO GTPases Activate NADPH Oxidases	5	152.3×	2e-08
VEGFA-VEGFR2 Pathway	5	46.4×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	23
Uncertain significance	183
Likely benign	319
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076527	NM_000433.4(NCF2):c.910C>T (p.Gln304Ter)	Pathogenic
1323334	NM_000433.4(NCF2):c.713+1G>A	Pathogenic
1378377	NM_000433.4(NCF2):c.830G>A (p.Trp277Ter)	Pathogenic
1408244	NM_000433.4(NCF2):c.30G>A (p.Trp10Ter)	Pathogenic
1446473	NM_000433.4(NCF2):c.251_254del (p.Thr84fs)	Pathogenic
1458116	NC_000001.11:g.183586978del	Pathogenic
1458778	NC_000001.10:g.(?183543602)(183543776_?)del	Pathogenic
1704874	NM_000433.4(NCF2):c.175-1G>A	Pathogenic
1952796	NM_000433.4(NCF2):c.65G>A (p.Trp22Ter)	Pathogenic
197669	NM_000433.4(NCF2):c.565C>T (p.Gln189Ter)	Pathogenic
2202893	NM_000433.4(NCF2):c.728del (p.Glu243fs)	Pathogenic
2202894	NM_000433.4(NCF2):c.574C>T (p.Gln192Ter)	Pathogenic
2239	NM_000433.4(NCF2):c.399_400dup (p.Lys134fs)	Pathogenic
2241	NM_000433.4(NCF2):c.304C>T (p.Arg102Ter)	Pathogenic
2242	NM_000433.4(NCF2):c.1171_1175del (p.Lys391fs)	Pathogenic
2243	NM_000433.4(NCF2):c.366+1G>A	Pathogenic
2245	NM_000433.4(NCF2):c.55_63del (p.Lys19_Asp21del)	Pathogenic
2423085	NC_000001.10:g.(?183542300)(183542447_?)del	Pathogenic
2581423	NM_000433.4(NCF2):c.1099C>T (p.Gln367Ter)	Pathogenic
2697516	NM_000433.4(NCF2):c.1165_1171del (p.His389fs)	Pathogenic
2702941	NM_000433.4(NCF2):c.2T>C (p.Met1Thr)	Pathogenic
2734054	NM_000433.4(NCF2):c.1038_1039del (p.Ser347fs)	Pathogenic
2734055	NM_000433.4(NCF2):c.475del (p.Ile159fs)	Pathogenic
2734056	NM_000433.4(NCF2):c.229C>T (p.Arg77Ter)	Pathogenic
2769198	NC_000001.11:g.183563586del	Pathogenic
2770552	NM_000433.4(NCF2):c.236del (p.Met79fs)	Pathogenic
2786568	NM_000433.4(NCF2):c.172A>T (p.Lys58Ter)	Pathogenic
2791776	NM_000433.4(NCF2):c.343C>T (p.Gln115Ter)	Pathogenic
2842274	NM_000433.4(NCF2):c.873C>A (p.Cys291Ter)	Pathogenic
2860010	NM_000433.4(NCF2):c.246C>A (p.Tyr82Ter)	Pathogenic

SpliceAI

2216 predictions. Top by Δscore:

Variant	Effect	Δscore
1:183560091:CTTA:C	donor_loss	1.0000
1:183560092:TTACC:T	donor_loss	1.0000
1:183560093:TACCC:T	donor_loss	1.0000
1:183560094:A:AC	donor_gain	1.0000
1:183560094:AC:A	donor_gain	1.0000
1:183560094:ACC:A	donor_gain	1.0000
1:183560095:C:CC	donor_gain	1.0000
1:183560095:CC:C	donor_gain	1.0000
1:183560095:CCC:C	donor_gain	1.0000
1:183560095:CCCT:C	donor_gain	1.0000
1:183560095:CCCTT:C	donor_gain	1.0000
1:183560125:T:TA	donor_gain	1.0000
1:183560269:TCACC:T	acceptor_gain	1.0000
1:183560270:CACC:C	acceptor_gain	1.0000
1:183560270:CACCC:C	acceptor_gain	1.0000
1:183560271:ACC:A	acceptor_gain	1.0000
1:183560272:CC:C	acceptor_gain	1.0000
1:183560272:CCC:C	acceptor_gain	1.0000
1:183560273:CC:C	acceptor_gain	1.0000
1:183560273:CCTGA:C	acceptor_loss	1.0000
1:183560274:C:CC	acceptor_gain	1.0000
1:183560274:C:T	acceptor_gain	1.0000
1:183563187:GCACT:G	donor_loss	1.0000
1:183563188:CACTC:C	donor_loss	1.0000
1:183563189:ACTC:A	donor_loss	1.0000
1:183563190:CT:C	donor_loss	1.0000
1:183563191:T:TA	donor_loss	1.0000
1:183563192:C:CG	donor_loss	1.0000
1:183563193:A:AC	donor_gain	1.0000
1:183563194:C:CC	donor_gain	1.0000

AlphaMissense

3476 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:183566978:A:T	V289D	0.999
1:183567220:A:T	V280D	0.998
1:183567259:A:T	V267D	0.998
1:183570798:A:C	F217L	0.998
1:183570798:A:T	F217L	0.998
1:183570800:A:G	F217L	0.998
1:183566963:A:G	L294P	0.997
1:183566963:A:T	L294H	0.997
1:183567227:C:G	A278P	0.997
1:183567255:A:C	F268L	0.997
1:183567255:A:T	F268L	0.997
1:183567257:A:G	F268L	0.997
1:183586922:C:G	R77P	0.997
1:183590293:C:A	G13W	0.996
1:183590302:A:G	W10R	0.996
1:183590302:A:T	W10R	0.996
1:183556219:A:G	W494R	0.995
1:183556219:A:T	W494R	0.995
1:183570807:G:C	F214L	0.995
1:183570807:G:T	F214L	0.995
1:183570809:A:G	F214L	0.995
1:183570838:A:T	V204D	0.995
1:183573246:A:G	F183S	0.995
1:183577624:A:G	L114P	0.995
1:183577663:A:G	L101P	0.995
1:183586963:G:C	S63R	0.995
1:183586963:G:T	S63R	0.995
1:183586965:T:G	S63R	0.995
1:183590204:G:C	N42K	0.995
1:183590204:G:T	N42K	0.995

dbSNP variants (sampled 300 via entrez): RS1000048232 (1:183573959 A>G), RS1000084883 (1:183595208 C>T), RS1000185935 (1:183567302 G>A), RS1000247159 (1:183574295 C>T), RS1000262649 (1:183584553 G>A), RS1000265592 (1:183591309 T>A), RS1000304880 (1:183560356 C>T), RS1000305887 (1:183574767 A>G,T), RS1000515892 (1:183596776 T>C), RS1000551060 (1:183580498 G>A), RS1000569857 (1:183597140 C>A,T), RS1000688871 (1:183596690 C>T), RS1000729486 (1:183591425 C>A,T), RS1000794727 (1:183590846 G>A), RS1000797526 (1:183584861 C>A,T)

Disease associations

OMIM: gene MIM:608515 | disease phenotypes: MIM:233710, MIM:306400, MIM:616211

GenCC curated gene-disease

Disease	Classification	Inheritance
granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	Definitive	Autosomal recessive
chronic granulomatous disease	Supportive	Autosomal recessive

Mondo (3): granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (MONDO:0009310), chronic granulomatous disease (MONDO:0018305), developmental and epileptic encephalopathy, 28 (MONDO:0014533)

Orphanet (2): Chronic granulomatous disease (Orphanet:379), Non-specific early-onset epileptic encephalopathy (Orphanet:442835)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000230	Gingivitis
HP:0000246	Sinusitis
HP:0000388	Otitis media
HP:0000964	Eczematoid dermatitis
HP:0000992	Cutaneous photosensitivity
HP:0001034	Hypermelanotic macule
HP:0001287	Meningitis
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001874	Abnormality of neutrophils
HP:0001945	Fever
HP:0002021	Pyloric stenosis
HP:0002024	Malabsorption
HP:0002037	Inflammation of the large intestine
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002575	Tracheoesophageal fistula
HP:0002586	Peritonitis
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002722	Recurrent abscess formation
HP:0002723	Absence of bactericidal oxidative respiratory burst in phagocytes
HP:0002724	Recurrent Aspergillus infections
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002740	Recurrent E. coli infections
HP:0002741	Recurrent Serratia marcescens infections
HP:0002742	Recurrent Klebsiella infections

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003155_39	Systemic lupus erythematosus	3.000000e-88
GCST003156_19	Systemic lupus erythematosus	2.000000e-59
GCST003252_10	Systemic lupus erythematosus	3.000000e-08
GCST003622_68	Systemic lupus erythematosus	2.000000e-59
GCST004867_12	Systemic lupus erythematosus	1.000000e-07
GCST005752_18	Systemic lupus erythematosus	6.000000e-11
GCST007278_6	Systemic seropositive rheumatic diseases (Systemic sclerosis or systemic lupus erythematosus or rheumatoid arthritis or idiopathic inflammatory myopathies)	4.000000e-15
GCST008644_22	Celiac disease and Rheumatoid arthritis	1.000000e-14
GCST010064_1	Celiac disease	2.000000e-16
GCST011956_58	Systemic lupus erythematosus	2.000000e-14

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006105	Granulomatous Disease, Chronic	C15.378.553.774.535; C16.320.322.233; C20.673.774.535; C23.550.291.500.423
C565531	Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome B-Positive, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects reaction, increases expression, increases abundance, increases phosphorylation	9
Benzo(a)pyrene	increases expression	6
Aflatoxin B1	affects expression, increases expression, increases methylation	5
Tobacco Smoke Pollution	affects localization, increases activity, increases expression	4
Cyclosporine	decreases expression, increases expression	4
bisphenol A	decreases expression, increases expression	3
monomethylarsonous acid	increases expression	3
Arsenic Trioxide	increases cleavage, increases phosphorylation, affects localization, increases expression, decreases reaction (+1 more)	3
Estradiol	affects expression, affects cotreatment, increases expression	3
Formaldehyde	decreases expression, increases expression	3
Cadmium Chloride	increases abundance, increases expression	3
methyleugenol	increases expression	2
cupric chloride	increases expression	2
(+)-JQ1 compound	decreases expression	2
Air Pollutants	increases abundance, increases expression	2
Dichlorodiphenyl Dichloroethylene	increases expression, decreases expression	2
N-Nitrosopyrrolidine	increases expression	2
Nickel	decreases expression, increases expression	2
Ozone	increases abundance, increases expression	2
Quercetin	decreases reaction, increases expression	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Tetradecanoylphorbol Acetate	decreases reaction, affects reaction, increases expression, affects localization	2
Tretinoin	increases expression	2
Fenretinide	increases expression	2
Raloxifene Hydrochloride	affects reaction, decreases expression, affects expression, affects cotreatment	2
TL8-506	affects cotreatment, increases expression	1
diminazene aceturate	decreases transport	1
2,4,6-tribromophenol	increases expression	1
ethylbenzene	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_V329	CHO-91-22-47-67	Spontaneously immortalized cell line	Female
CVCL_V330	CHO-91-47-67	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001317	PHASE4	COMPLETED	A Phase IV Study of Recombinant Human Gamma Interferon in Patients With Chronic Granulomatous Diseases of Childhood
NCT00023192	PHASE3	COMPLETED	Treatment of Chronic Granulomatous Disease With Allogeneic Stem Cell Transplantation Versus Standard of Care
NCT00033982	PHASE3	COMPLETED	Posaconazole to Treat Invasive Fungal Infections
NCT00006417	PHASE2	COMPLETED	Modified Stem Cell Transplantation Procedure for Treating Chronic Granulomatous Disease
NCT00578643	PHASE2	COMPLETED	Matched Unrelated or Non-Genotype Identical Related Donor Transplantation For Chronic Granulomatous Disease
NCT00799071	PHASE2	COMPLETED	Pharmacokinetics of Posaconazole in Children With Chronic Granulomatous Disease (CGD)
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT01998633	PHASE2	COMPLETED	Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT03547830	PHASE2	UNKNOWN	Plerixafor/G-CSF as Additional Agents for Conditioning Before HSCT in CGD Patients
NCT03983837	PHASE2	COMPLETED	Elemental Diet for Treatment of Inflammatory Bowel Disease in Patients With Chronic Granulomatous Disease
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00001476	PHASE1	COMPLETED	Gene Therapy for Chronic Granulomatous Diseases - Long-term Follow-up
NCT00001515	PHASE1	COMPLETED	Diagnostic Effectiveness of Virtual Bronchoscopy
NCT00001765	PHASE1	COMPLETED	Stem Cell Transplant Following Low-Intensity Chemotherapy to Treat Chronic Granulomatous Disease
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT02609932	PHASE1	COMPLETED	Effect of IFN-γ on Innate Immune Cells
NCT05189925	PHASE1	RECRUITING	NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD)
NCT03984890	PHASE2/PHASE3	COMPLETED	Vitamin D3 For CGD Patients With BCGosis/Itis
NCT00325078	PHASE1/PHASE2	TERMINATED	Infliximab to Treat Crohn’S-like Inflammatory Bowel Disease in Chronic Granulomatous Disease
NCT00564759	PHASE1/PHASE2	UNKNOWN	Gene Therapy for Chronic Granulomatous Disease
NCT00778882	PHASE1/PHASE2	WITHDRAWN	Gene Therapy for Chronic Granulomatous Disease in Korea
NCT00927134	PHASE1/PHASE2	COMPLETED	Gene Therapy for X-linked Chronic Granulomatous Disease (CGD) in Children
NCT01338675	PHASE1/PHASE2	UNKNOWN	Targeted Busulfan, Fludarabine Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Chronic Granulomatous Disease(CGD)
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02282904	PHASE1/PHASE2	TERMINATED	Haploidentical Transplant for People With Chronic Granulomatous Disease Using Post Transplant Cyclophosphamide
NCT03080480	PHASE1/PHASE2	TERMINATED	Pioglitazone Therapy for Chronic Granulomatous Disease
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT05104723	PHASE1/PHASE2	COMPLETED	Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications
NCT05463133	PHASE1/PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease (CGD) With an Alemtuzumab, Busulfan and TBI-based Conditioning Regimen Combined With Cytokine (IL-6, +/- IFN-gamma) Antagonists
NCT06253507	PHASE1/PHASE2	ENROLLING_BY_INVITATION	pCCLCHIM-p47 (Lentiviral Vector Transduced CD34 Plus Cells) in Patients With p47 Autosomal Recessive Chronic Granulomatous Disease (AR-CGD)
NCT06325709	PHASE1/PHASE2	RECRUITING	Base Editing for Mutation Repair in Hematopoietic Stem & Progenitor Cells for X-Linked Chronic Granulomatous Disease
NCT06559176	PHASE1/PHASE2	ENROLLING_BY_INVITATION	A Study of the Safety and Efficacy of Prime Editing (PM359) in Participants With p47phox Autosomal Recessive Chronic Granulomatous Disease (CGD )
NCT07113743	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Part B- G1X-CGD (Lentiviral Vector Transduced CD34+ Cells) in Patients With X-Linked Chronic Granulomatous Disease
NCT00394316	EARLY_PHASE1	TERMINATED	Gene Therapy for Chronic Granulomatous Disease
NCT03910452	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Haploidentical Transplant for People With Chronic Granulomatous Disease (CGD) Using Alemtuzumab, Busulfan and TBI With Post-Transplant Cyclophosphamide
NCT03921515	EARLY_PHASE1	WITHDRAWN	Skin Immunity Sample Collection Involving Blisters and Biopsies
NCT04136028	EARLY_PHASE1	COMPLETED	IL-1 Receptor Inhibitor for Granulomatous Complications in Patients With Chronic Granulomatous Disease
NCT05600907	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Study to Assess the Use of JSP191 in Matched Unrelated Donor Transplantation for Chronic Granulomatous Disease (CGD)