NCF4

Summary

NCF4 (neutrophil cytosolic factor 4, HGNC:7662) is a protein-coding gene on chromosome 22q12.3, encoding Neutrophil cytosol factor 4 (Q15080). Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)).

The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 4689 — RefSeq curated summary.

At a glance

• Gene–disease (curated): granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 428 total — 15 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 34
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000631

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7662
Approved symbol	NCF4
Name	neutrophil cytosolic factor 4
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	p40phox, SH3PXD4
Ensembl gene	ENSG00000100365
Ensembl biotype	protein_coding
OMIM	601488
Entrez	4689

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000248899, ENST00000397147, ENST00000415063, ENST00000447071, ENST00000650698, ENST00000650827, ENST00000651053

RefSeq mRNA: 2 — MANE Select: NM_000631 NM_000631, NM_013416

CCDS: CCDS13934, CCDS13935

Canonical transcript exons

ENST00000248899 — 10 exons

Exon	Start	End
ENSE00000653691	36872327	36872425
ENSE00000653693	36876029	36876094
ENSE00000880088	36870415	36870542
ENSE00000880089	36871652	36871709
ENSE00001270603	36875653	36875783
ENSE00001766180	36864045	36864129
ENSE00003488791	36864919	36865072
ENSE00003570206	36877628	36878015
ENSE00003675854	36867392	36867462
ENSE00003845550	36861006	36861203

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 99.04.

FANTOM5 (CAGE): breadth broad, TPM avg 22.8893 / max 2008.0993, expressed in 550 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192066	16.9228	539
192067	3.4826	400
192068	1.7589	301
192065	0.6358	224
192064	0.0410	12
192069	0.0252	6
192070	0.0230	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	99.04	gold quality
spleen	UBERON:0002106	97.55	gold quality
granulocyte	CL:0000094	97.43	gold quality
bone marrow	UBERON:0002371	97.43	gold quality
monocyte	CL:0000576	97.03	gold quality
leukocyte	CL:0000738	97.00	gold quality
bone marrow cell	CL:0002092	96.73	gold quality
vermiform appendix	UBERON:0001154	95.12	gold quality
lymph node	UBERON:0000029	94.18	gold quality
layer of synovial tissue	UBERON:0007616	92.43	gold quality
placenta	UBERON:0001987	92.00	gold quality
right lung	UBERON:0002167	90.78	gold quality
upper lobe of left lung	UBERON:0008952	90.33	gold quality
right coronary artery	UBERON:0001625	89.37	gold quality
omental fat pad	UBERON:0010414	88.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.66	gold quality
gall bladder	UBERON:0002110	87.75	gold quality
mucosa of transverse colon	UBERON:0004991	87.69	gold quality
small intestine	UBERON:0002108	87.55	gold quality
adipose tissue	UBERON:0001013	86.82	gold quality
lung	UBERON:0002048	86.01	gold quality
right adrenal gland cortex	UBERON:0035827	85.39	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.23	gold quality
rectum	UBERON:0001052	85.02	gold quality
duodenum	UBERON:0002114	84.55	gold quality
transverse colon	UBERON:0001157	84.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.92	gold quality
apex of heart	UBERON:0002098	83.68	gold quality
right adrenal gland	UBERON:0001233	83.22	gold quality
left coronary artery	UBERON:0001626	83.04	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	49.05
E-ANND-3	yes	18.34
E-MTAB-9067	yes	11.41
E-CURD-120	no	30.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, SPI1

miRNA regulators (miRDB)

11 targeting NCF4, 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-551B-5P	99.96	71.28	3493
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-411-5P	97.11	66.82	601
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-4524B-3P	95.52	64.12	964

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 34)

• 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)
• Involvement of protein kinase D in Fc gamma-receptor activation of the NADPH oxidase in neutrophils (PMID:11903052)
• Multiple PU.1 sites cooperate in the regulation of p40(phox) transcription during granulocytic differentiation of myeloid cells. (PMID:12036891)
• p40phox and p47phox PX domains interact with PI-containing membranes (PMID:12556460)
• A model is proposed in which phosphorylation of p40PHOX on threonine 154 leads to an inhibitory conformation that shifts the balance toward an inhibitory role and blocks NADPH oxidase activation. (PMID:15035643)
• review of p40phox role in NADPH oxidase dynamics and possible non-NADPH oxidase processes in phagocytic and non-phagocytic cells (PMID:16102984)
• This study identifies a role for p40(phox) and PI(3)P in coupling FcgammaR-mediated phagocytosis to activation of the NADPH oxidase. (PMID:16880255)
• analysis of the dual regulatory mechanism through the PX domain of p40(phox): its interaction with the actin cytoskeleton may stabilize NADPH oxidase in resting cells, and binding of PtdIns (3)P potentiates superoxide production upon agonist stimulation (PMID:17698849)
• In Swedish men with rheumatoid arthritis there were several single nucleotide polymorphisms identified in NCF4. (PMID:17897462)
• This study has confirmed NCF4 and IRGM are risk factors for ileal Crohn’s disease in New Zealand Caucasians. (PMID:18580884)
• p40(phox) functions primarily to regulate Fc gamma receptor-induced NADPH oxidase activity rather than assembly, and stimulates superoxide production via a phosphatidylinositol-3-phosphate signal that increases after phagosome internalization. (PMID:18711001)
• Class III PI3K Vps34 is responsible for the synthesis of PtdIns(3)P on phagosomes containing either S aureus or E coli. PtdIns(3)P binding to p40(phox) is important for CD18-dependent activation oxidase activation in response to S aureus and E coli (PMID:18755982)
• regulates activity of NADPH oxidase which generates superoxide production in neutrophils. (review) (PMID:18807499)
• p40(phox) binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease. (PMID:19692703)
• All mutations and some polymorphisms identified in the NCF4 gene in the autosomal forms of chronic granulomatous disease are listed. Review. (PMID:20167518)
• cytosolic localisation depends on direct interaction with F-actin (PMID:20637895)
• no association between SNP rs4821544 and the presence of granulomas in Crohn’s disease (PMID:21122541)
• Genome-wide association studies-reported associations between the NELL1, NCF4, and FAM92B genes and susceptibility to Crohn’s disease could not be replicated in Canadian children and young adults. (PMID:21472827)
• Results demonstrate that PBEF can prime for PMN respiratory burst activity by promoting p40 and p47 translocation to the membrane. (PMID:21518975)
• cooperation of p40(phox) with p47(phox) for Nox2-based NADPH oxidase activation during Fcgamma receptor (FcgammaR)-mediated phagocytosis (PMID:21956105)
• Younger age at diagnosis, complicated disease behavior, and ileal disease location are risk factors for perianal CD. First report of an association of the NCF4 gene with perianal disease. (PMID:22158027)
• Constitutive and inducible intracellular production of reactive oxygen species (ROS) is higher in B cells expressing functional p40phox, supporting a direct role for p40phox in regulating B cell intracellular ROS generation. (PMID:22984083)
• The contribution of the functionally relevant NADPH polymorphisms rs1883112 and rs4673 to anthracycline-related heart lesions provides a plausible explanation for their modulation of cardiotoxicity. (PMID:23576480)
• Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer. (PMID:23982929)
• NCF4 may induce ex- pression of NADPH oxidase enzymes, such as p67phox, p47phox, p22phox and NOX2, which lead to increased ROS levels. (PMID:24378533)
• NCF4 polymorphism was associated with Crohn’s disease, but not ulcerative colitis in Caucasian–{REVIEW} (PMID:26289093)
• Phosphoinositol 3-phosphate regulates reactive oxygen species production by maintaining p40phox and p67phox at the phagosomal membrane. (PMID:28096301)
• Tyrosine kinase substrate (Tks) proteins, analogous to the related proteins p47(phox), p40(phox) and NoxO1, also facilitate local generation of reactive oxygen species (ROS), which aid in signaling at invadopodia and/or podosomes to promote their activity. As their name suggests, Tks adaptor proteins are substrates for tyrosine kinases, especially Src. [review] (PMID:29311151)
• We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. (PMID:29969437)
• Association of NCF2, NCF4, and CYBA Gene Polymorphisms with Rheumatoid Arthritis in a Chinese Population. (PMID:33145364)
• NCF1/2/4 Are Prognostic Biomarkers Related to the Immune Infiltration of Kidney Renal Clear Cell Carcinoma. (PMID:34708124)
• Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus. (PMID:38085396)
• NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance. (PMID:38886341)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ncf4	ENSDARG00000040812
mus_musculus	Ncf4	ENSMUSG00000071715
rattus_norvegicus	Ncf4	ENSRNOG00000006940
drosophila_melanogaster	Dlish	FBGN0034264
caenorhabditis_elegans		WBGENE00012891
caenorhabditis_elegans		WBGENE00015128

Paralogs (12): SORBS1 (ENSG00000095637), SH3GLB1 (ENSG00000097033), SH3GL2 (ENSG00000107295), SH3D19 (ENSG00000109686), SORBS3 (ENSG00000120896), SH3GL3 (ENSG00000140600), SH3GL1 (ENSG00000141985), SH3GLB2 (ENSG00000148341), SH3RF1 (ENSG00000154447), SORBS2 (ENSG00000154556), SH3RF2 (ENSG00000156463), SH3RF3 (ENSG00000172985)

Protein

Protein identifiers

Neutrophil cytosol factor 4 — Q15080 (reviewed: Q15080)

Alternative names: Neutrophil NADPH oxidase factor 4, SH3 and PX domain-containing protein 4, p40-phox

All UniProt accessions (3): Q15080, A0A494BZS1, B0QY04

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 NCF2 and NCF1. The NCF2-NCF4 complex interacts with GBP7 (via GB1/RHD3-type G domain).

Subcellular location. Cytoplasm. Cytosol. Endosome membrane. Membrane.

Tissue specificity. Expression is restricted to hematopoietic cells.

Disease relevance. Granulomatous disease, chronic, autosomal recessive, 3 (CGD3) [MIM:613960] 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 PB1 domain mediates the association with NCF2/p67-PHOX. The PX domain mediates interaction with membranes enriched in phosphatidylnositol 3-phosphate.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15080-1	1	yes
Q15080-3	3

RefSeq proteins (2): NP_000622, NP_038202 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000270	PB1_dom	Domain
IPR000919	p40phox	Family
IPR001452	SH3_domain	Domain
IPR001683	PX_dom	Domain
IPR034853	PB1_P40	Domain
IPR034912	PX_p40phox	Domain
IPR035541	p40phox_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036871	PX_dom_sf	Homologous_superfamily
IPR051228	NADPH_Oxidase/PX-Domain	Family
IPR053793	PB1-like	Domain

Pfam: PF00018, PF00564, PF00787

UniProt features (50 total): strand 16, mutagenesis site 11, helix 10, sequence variant 4, domain 3, binding site 2, modified residue 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1W70	X-RAY DIFFRACTION	1.46
1H6H	X-RAY DIFFRACTION	1.7
1OEY	X-RAY DIFFRACTION	2
1W6X	X-RAY DIFFRACTION	2
2DYB	X-RAY DIFFRACTION	3.15
1Z9Q	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15080-F1	84.48	0.48

Functional residue map

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

Ligand- & substrate-binding residues (2): 58–60; 92–94

Post-translational modifications (2): 154, 315

Mutagenesis-validated functional residues (11):

Position	Phenotype
58	abolishes interaction with membranes enriched in phosphatidylinositol 3-phosphate.
60	strongly reduces interaction with membranes enriched in phosphatidylinositol 3-phosphate.
92	abolishes interaction with membranes enriched in phosphatidylinositol 3-phosphate.
94	slightly reduces interaction with membranes enriched in phosphatidylinositol 3-phosphate.
105	abolishes interaction with membranes enriched in phosphatidylinositol 3-phosphate.
154	reduces phosphorylation.
211	no effect on phosphorylation.
251	no effect on phosphorylation.
274	no effect on phosphorylation.
315	reduces phosphorylation.
327	no effect on phosphorylation.

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: 377 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, MODULE_45, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_16, CAGCTG_AP4_Q5, GOLDRATH_ANTIGEN_RESPONSE, MODULE_75, GOBP_RESPIRATORY_BURST, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_UP, MODULE_165

GO Biological Process (3): phagocytosis (GO:0006909), superoxide anion generation (GO:0042554), respiratory burst (GO:0045730)

GO Molecular Function (5): superoxide-generating NADPH oxidase activator activity (GO:0016176), phosphatidylinositol-3-phosphate binding (GO:0032266), protein binding (GO:0005515), lipid binding (GO:0008289), phosphatidylinositol binding (GO:0035091)

GO Cellular Component (8): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), phagolysosome (GO:0032010), NADPH oxidase complex (GO:0043020), endosome (GO:0005768)

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
binding	2
endocytosis	1
superoxide metabolic process	1
metabolic process	1
enzyme activator activity	1
superoxide-generating NADPH oxidase activity	1
phosphatidylinositol phosphate binding	1
anion binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
secondary lysosome	1
phagocytic vesicle	1
plasma membrane protein complex	1
oxidoreductase complex	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

2724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCF4	CYBA	P13498	999
NCF4	CYBB	P04839	999
NCF4	RAC2	P15153	997
NCF4	NOXA1	Q86UR1	995
NCF4	NOXO1	Q8NFA2	995
NCF4	AKT1	P31749	992
NCF4	NCF2	P19878	991
NCF4	NOX1	Q9Y5S8	991
NCF4	NCF1	P14598	990
NCF4	NOX4	Q9NPH5	971
NCF4	DUOX1	Q9NRD9	933
NCF4	RAP1A	P10113	912
NCF4	NOX5	Q96PH1	860
NCF4	NOX3	Q9HBY0	856
NCF4	DUOX2	Q9NRD8	830

IntAct

12 interactions, top by confidence:

A	B	Type	Score
NCF4	NCF2	psi-mi:“MI:0407”(direct interaction)	0.800
NCF4	NCF2	psi-mi:“MI:0915”(physical association)	0.800
NCF2	NCF4	psi-mi:“MI:0915”(physical association)	0.800
NCF2	GNAI2	psi-mi:“MI:0914”(association)	0.580
NCF1	NCF4	psi-mi:“MI:0407”(direct interaction)	0.560
NCF4	NCF1	psi-mi:“MI:0407”(direct interaction)	0.560
NCF4	CYBA	psi-mi:“MI:0407”(direct interaction)	0.440
CYBA	NCF4	psi-mi:“MI:0407”(direct interaction)	0.440
MLH1	NCF4	psi-mi:“MI:0915”(physical association)	0.370
NCF4	gatA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): NCF4 (Two-hybrid), NCF4 (Co-fractionation), NCF4 (Affinity Capture-Western), NCF4 (Reconstituted Complex), NCF4 (Reconstituted Complex), NCF4 (Proximity Label-MS), NCF4 (Affinity Capture-Western), NCF4 (Reconstituted Complex), NCF4 (Reconstituted Complex), NCF2 (Two-hybrid), NCF1 (Two-hybrid), XRCC6 (Reconstituted Complex), NCF4 (Biochemical Activity), NCF4 (Reconstituted Complex), NCF4 (Affinity Capture-RNA)

ESM2 similar proteins: B2RZ59, F1LYQ8, F1P065, F8VPU2, O14796, O35324, O60880, O75791, O88890, O88900, O89100, O94887, P0CE43, P46108, P46109, P47941, P52735, P59622, P87378, P97369, Q03160, Q04929, Q06AA1, Q13239, Q13322, Q14449, Q15080, Q1RMW5, Q2I6J1, Q3ZBB1, Q45HK4, Q5ICW4, Q5RAB8, Q5U2U2, Q60760, Q60898, Q60992, Q63768, Q64010, Q6P4S2

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

3 interactions.

A	Effect	B	Mechanism
PRKCD	“up-regulates activity”	NCF4	phosphorylation
PRKCA	“up-regulates activity”	NCF4	phosphorylation
NCF4	“form complex”	“Phagocyte NADPH oxidase complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	7
Uncertain significance	167
Likely benign	166
Benign	45

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1933256	NM_000631.5(NCF4):c.256del (p.Leu86fs)	Pathogenic
1991035	NM_000631.5(NCF4):c.759-19C>T	Pathogenic
2085367	NM_000631.5(NCF4):c.758+28_758+29insA	Pathogenic
222998	NM_000631.5(NCF4):c.143_152dup (p.Lys52fs)	Pathogenic
2429239	NM_000631.5(NCF4):c.759-40C>T	Pathogenic
2696736	NM_000631.5(NCF4):c.758+36_758+81del	Pathogenic
2762518	NM_000631.5(NCF4):c.367del (p.Val123fs)	Pathogenic
2828193	NM_000631.5(NCF4):c.456del (p.Arg153fs)	Pathogenic
2834848	NM_000631.5(NCF4):c.759-24T>G	Pathogenic
30193	NM_000631.5(NCF4):c.143_152del (p.Lys48fs)	Pathogenic
30194	NM_000631.5(NCF4):c.314G>A (p.Arg105Gln)	Pathogenic
3605021	NM_000631.5(NCF4):c.13C>T (p.Gln5Ter)	Pathogenic
4695244	NM_000631.5(NCF4):c.771G>A (p.Val257=)	Pathogenic
932309	NM_000631.5(NCF4):c.716G>A (p.Trp239Ter)	Pathogenic
932310	NM_000631.5(NCF4):c.32+2T>G	Pathogenic
1192210	NM_000631.5(NCF4):c.33-1G>A	Likely pathogenic
2504047	NM_000631.5(NCF4):c.471-1G>A	Likely pathogenic
3588030	NM_000631.5(NCF4):c.3G>A (p.Met1Ile)	Likely pathogenic
3588031	NM_000631.5(NCF4):c.32+2T>C	Likely pathogenic
3654709	NM_000631.5(NCF4):c.470+2T>G	Likely pathogenic
803685	NC_000022.11:g.36864921_36864935del	Likely pathogenic
842976	NM_000631.5(NCF4):c.270_271+16del	Likely pathogenic

SpliceAI

1106 predictions. Top by Δscore:

Variant	Effect	Δscore
22:36861200:AGAGG:A	donor_loss	1.0000
22:36861201:GAG:G	donor_gain	1.0000
22:36861202:AGGT:A	donor_loss	1.0000
22:36861203:GGTG:G	donor_loss	1.0000
22:36861204:GTGA:G	donor_loss	1.0000
22:36864038:C:CA	acceptor_gain	1.0000
22:36864041:ACAGT:A	acceptor_gain	1.0000
22:36864042:C:G	acceptor_gain	1.0000
22:36864044:GT:G	acceptor_gain	1.0000
22:36864130:G:GG	donor_gain	1.0000
22:36864914:CTTA:C	acceptor_loss	1.0000
22:36864915:TTA:T	acceptor_loss	1.0000
22:36864916:TA:T	acceptor_loss	1.0000
22:36864917:A:AC	acceptor_loss	1.0000
22:36864917:A:AG	acceptor_gain	1.0000
22:36864918:G:GG	acceptor_gain	1.0000
22:36864918:G:GT	acceptor_loss	1.0000
22:36864918:GGTT:G	acceptor_gain	1.0000
22:36865074:T:A	donor_loss	1.0000
22:36867391:GCCAA:G	acceptor_gain	1.0000
22:36870405:A:AG	acceptor_gain	1.0000
22:36870410:CACA:C	acceptor_loss	1.0000
22:36870411:ACAG:A	acceptor_loss	1.0000
22:36870412:CA:C	acceptor_loss	1.0000
22:36870414:GA:G	acceptor_gain	1.0000
22:36870414:GAGCC:G	acceptor_gain	1.0000
22:36870538:A:T	donor_gain	1.0000
22:36870539:AAGT:A	donor_gain	1.0000
22:36870541:GT:G	donor_gain	1.0000
22:36870543:G:GG	donor_gain	1.0000

AlphaMissense

2229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:36864970:C:A	R57S	0.998
22:36864083:C:A	A24D	0.997
22:36864971:G:C	R57P	0.997
22:36864986:T:C	F62S	0.997
22:36872417:T:A	W207R	0.996
22:36872417:T:C	W207R	0.996
22:36875653:G:C	G210R	0.996
22:36877767:T:A	W322R	0.996
22:36877767:T:C	W322R	0.996
22:36867425:C:A	A102D	0.995
22:36872339:T:C	F181L	0.994
22:36872341:C:A	F181L	0.994
22:36872341:C:G	F181L	0.994
22:36875692:T:C	F223L	0.994
22:36875694:C:A	F223L	0.994
22:36875694:C:G	F223L	0.994
22:36864922:T:C	F41L	0.993
22:36864924:C:A	F41L	0.993
22:36864924:C:G	F41L	0.993
22:36872364:T:C	L189P	0.993
22:36864089:T:A	I26N	0.992
22:36872419:G:C	W207C	0.992
22:36872419:G:T	W207C	0.992
22:36877661:T:A	N286K	0.992
22:36877661:T:G	N286K	0.992
22:36864970:C:G	R57G	0.991
22:36867446:T:C	L109P	0.991
22:36875654:G:A	G210D	0.991
22:36864082:G:C	A24P	0.990
22:36870419:T:C	L116P	0.990

dbSNP variants (sampled 300 via entrez): RS1000282241 (22:36859181 C>A), RS1000384993 (22:36863534 C>A,T), RS1000437315 (22:36863457 C>A,T), RS1000679519 (22:36862789 A>G), RS1000820930 (22:36867252 G>A), RS1001000475 (22:36868475 G>A), RS1001056673 (22:36878339 C>T), RS1001166777 (22:36870405 A>C), RS1001200546 (22:36873217 G>A,C), RS1001787956 (22:36859577 G>T), RS1001788354 (22:36864288 C>T), RS1001835888 (22:36864080 C>G,T), RS1001997832 (22:36872910 G>A), RS1002132088 (22:36859830 G>A), RS1002152129 (22:36874952 T>C)

Disease associations

OMIM: gene MIM:601488 | disease phenotypes: MIM:613960, MIM:306400

GenCC curated gene-disease

Disease	Classification	Inheritance
granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	Strong	Autosomal recessive
chronic granulomatous disease	Supportive	Autosomal recessive

Mondo (2): granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3 (MONDO:0013507), chronic granulomatous disease (MONDO:0018305)

Orphanet (1): Chronic granulomatous disease (Orphanet:379)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
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:0001744	Splenomegaly
HP:0001874	Abnormality of neutrophils
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002021	Pyloric stenosis
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002575	Tracheoesophageal fistula
HP:0002583	Colitis
HP:0002719	Recurrent infections
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0005218	Anoperineal fistula
HP:0006510	Chronic pulmonary obstruction
HP:0011107	Recurrent aphthous stomatitis
HP:0011108	Recurrent sinusitis
HP:0011127	Perioral eczema
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011463	Childhood onset
HP:0012733	Macule
HP:0100523	Liver abscess

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001363_5	Atopic dermatitis	6.000000e-06
GCST003602_5	Inflammatory bowel disease	8.000000e-07
GCST004132_55	Crohn’s disease	2.000000e-08
GCST004600_121	Eosinophil percentage of white cells	4.000000e-12
GCST004606_99	Eosinophil count	5.000000e-13
GCST004617_45	Eosinophil percentage of granulocytes	9.000000e-11
GCST004623_44	Neutrophil percentage of granulocytes	6.000000e-10
GCST004624_31	Sum eosinophil basophil counts	5.000000e-14
GCST004862_108	Itch intensity from mosquito bite adjusted by bite size	6.000000e-09
GCST004865_4	Itch intensity from mosquito bite adjusted by bite size	3.000000e-07
GCST005531_73	Multiple sclerosis	1.000000e-06
GCST007122_6	Multiple sclerosis and triglyceride levels (pleiotropy)	4.000000e-06
GCST007732_10	Allergic disease (asthma, hay fever or eczema)	4.000000e-07
GCST007732_12	Allergic disease (asthma, hay fever or eczema)	9.000000e-06
GCST009597_173	Multiple sclerosis	5.000000e-11
GCST010042_89	Asthma	1.000000e-08
GCST90002381_442	Eosinophil count	4.000000e-16
GCST90002382_504	Eosinophil percentage of white cells	1.000000e-15

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1883112	Toxicity	3	doxorubicin;idarubicin	Neoplasms
rs1883112	Efficacy	3	idarubicin	Leukemia;Myeloid;Acute

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1883112	NCF4	3	3.75	2	doxorubicin;idarubicin;idarubicin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
2,3’,4,4’,5-pentachlorobiphenyl	increases expression, affects reaction	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Methotrexate	decreases expression, increases expression	2
Nickel	increases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
sodium bichromate	decreases expression	1
o,p’-DDT	increases expression, decreases reaction	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Bortezomib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diuron	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Methapyrilene	increases methylation	1
Paraquat	increases expression	1
Phthalic Acids	increases methylation	1
Quercetin	decreases reaction, increases expression	1
Tobacco Smoke Pollution	decreases methylation	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8L8	Abcam HCT 116 NCF4 KO	Cancer cell line	Male
CVCL_B9NE	Abcam A-549 NCF4 KO	Cancer cell line	Male
CVCL_D2GK	Abcam MCF-7 NCF4 KO	Cancer 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)