CSF3R

Summary

CSF3R (colony stimulating factor 3 receptor, HGNC:2439) is a protein-coding gene on chromosome 1p34.3, encoding Granulocyte colony-stimulating factor receptor (Q99062). Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. In precision oncology, CSF3R T618I confers sensitivity to Ruxolitinib in Chronic Neutrophilic Leukemia (CIViC Level C).

The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation, and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes. Alternatively spliced transcript variants have been described. Mutations in this gene are a cause of Kostmann syndrome, also known as severe congenital neutropenia.

Source: NCBI Gene 1441 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive severe congenital neutropenia due to CSF3R deficiency (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 38
• Clinical variants (ClinVar): 786 total — 30 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• MANE Select transcript: NM_000760

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2439
Approved symbol	CSF3R
Name	colony stimulating factor 3 receptor
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	GCSFR, G-CSF-R
Ensembl gene	ENSG00000119535
Ensembl biotype	protein_coding
OMIM	138971
Entrez	1441

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000373103, ENST00000373104, ENST00000373106, ENST00000464365, ENST00000464465, ENST00000466138, ENST00000469380, ENST00000480825, ENST00000484762, ENST00000487540, ENST00000489551, ENST00000526980, ENST00000533491, ENST00000699089, ENST00000699090, ENST00000699160, ENST00000909337, ENST00000909338, ENST00000909339, ENST00000944959, ENST00000944960, ENST00000944961, ENST00000944962, ENST00000944963

RefSeq mRNA: 3 — MANE Select: NM_000760 NM_000760, NM_156039, NM_172313

CCDS: CCDS412, CCDS413, CCDS414

Canonical transcript exons

ENST00000373106 — 17 exons

Exon	Start	End
ENSE00000000237	36482811	36482913
ENSE00000807433	36475377	36475673
ENSE00000807443	36467822	36467962
ENSE00001459523	36481478	36481537
ENSE00001633459	36466043	36466827
ENSE00003491116	36469156	36469257
ENSE00003501963	36467230	36467311
ENSE00003536478	36471433	36471646
ENSE00003548006	36479433	36479516
ENSE00003557128	36472238	36472391
ENSE00003565017	36473435	36473622
ENSE00003591626	36468075	36468221
ENSE00003600643	36469652	36469840
ENSE00003616645	36467558	36467651
ENSE00003618385	36472517	36472686
ENSE00003618998	36472066	36472139
ENSE00003631581	36473764	36473887

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 99.53.

FANTOM5 (CAGE): breadth broad, TPM avg 30.9174 / max 5737.9647, expressed in 489 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11754	17.1657	430
11752	8.3156	364
11753	4.1789	280
11743	0.4534	84
11750	0.1817	41
11747	0.1534	60
201469	0.1132	29
11749	0.1105	38
11748	0.0977	37
11751	0.0720	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.53	gold quality
monocyte	CL:0000576	99.20	gold quality
blood	UBERON:0000178	98.93	gold quality
leukocyte	CL:0000738	98.86	gold quality
mononuclear cell	CL:0000842	98.81	gold quality
upper lobe of left lung	UBERON:0008952	98.40	gold quality
right lung	UBERON:0002167	98.18	gold quality
upper lobe of lung	UBERON:0008948	97.94	gold quality
spleen	UBERON:0002106	97.64	gold quality
bone marrow cell	CL:0002092	94.43	gold quality
bone marrow	UBERON:0002371	94.13	gold quality
placenta	UBERON:0001987	93.42	gold quality
lower lobe of lung	UBERON:0008949	92.15	gold quality
trabecular bone tissue	UBERON:0002483	90.65	gold quality
vermiform appendix	UBERON:0001154	90.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.77	gold quality
gall bladder	UBERON:0002110	89.67	gold quality
omental fat pad	UBERON:0010414	89.22	gold quality
peritoneum	UBERON:0002358	89.16	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.46	gold quality
spinal cord	UBERON:0002240	87.35	gold quality
lung	UBERON:0002048	87.33	gold quality
caecum	UBERON:0001153	86.55	gold quality
right lobe of liver	UBERON:0001114	86.41	gold quality
left uterine tube	UBERON:0001303	85.95	gold quality
periodontal ligament	UBERON:0008266	84.13	gold quality
right coronary artery	UBERON:0001625	84.02	gold quality
apex of heart	UBERON:0002098	82.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.81	gold quality
right atrium auricular region	UBERON:0006631	82.79	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	3737.40
E-MTAB-6678	yes	2607.46
E-MTAB-9221	yes	2032.99
E-GEOD-149689	yes	1912.26
E-GEOD-130473	yes	1564.80
E-GEOD-150728	yes	1465.91
E-MTAB-9067	yes	955.32
E-MTAB-8884	yes	820.09
E-ANND-2	yes	362.32
E-HCAD-6	yes	184.63
E-MTAB-6701	yes	129.29
E-HCAD-1	yes	75.60
E-CURD-122	yes	65.73
E-HCAD-4	yes	62.03
E-GEOD-84465	yes	36.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPE, ETS1, ETS2, MAX, MYB, NFIA, SPI1, STAT5A

miRNA regulators (miRDB)

29 targeting CSF3R, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-3663-5P	97.01	64.84	713

Literature-anchored findings (GeneRIF, showing 40)

• the dimerization interface of the complete receptor complex is different from that in the x-ray structure of a partial complex. A model of the tetrameric G-CSF.G-CSF-R complex was prepared (PMID:11468284)
• The C-terminus of the G-CSF receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2-containing phosphatase-1 suppression of G-CSF-stimulated Stat activation. (PMID:11714811)
• Lack of STAT3beta function in a differentiation-competent murine cell line expressing human G-CSFR argues against its having a role in Kip1 expression or neutrophil differentiation. (PMID:11920194)
• Novel variant involved in induction of cell proliferation; myelodysplastic syndrome; a deletion of three nucleotides (2128-2130) in the juxtamembrane domain of the G-CSFR resulted in a conversion of Asn(630)Arg(631) to Lys(630). (PMID:12012328)
• abnormalities of primitive myeloid progenitor cells expressing G-CSFR may play an important role in the impairment of granulopoiesis in patients with severe congenital neutropenia (PMID:12422946)
• the carboxy-terminal region of hGCSFR plays a role in the phagocytosis and Syk and Hck kinase tyrosine phosphorylation is involved. (PMID:12586631)
• selective inhibition of G-CSF receptor expression by C/EBPalphap30-ER is due in part to its variable affinity for C/EBP sites (PMID:14737106)
• G-CSFR expression in some bladder cancers appears to be an early event during malignant transformation that increases beta1-integrin expression and adhesion and thereby may promote tissue invasion. (PMID:14751388)
• Thermodynamic data for the interaction of GCSF-GCSFR induced by GCSF binding suggest that the activated structure of GCSFR is a 2:2 complex structure. (PMID:14992583)
• reviewed the knowledge of the expression of G-CSFR and its role in the disorders of granulopoiesis, including myelodysplastic syndrome, and neutropenia in myelodysplastic patients (PMID:15370243)
• lifelong altered G-CSF response by the G-CSF-R_785Lys may render individuals susceptible to development of high-risk M (PMID:15644419)
• The Tyr 729 of the G-CSF-R is required for SOCS3-mediated negative regulation of G-CSF-R signaling and that the duration and intensity of G-CSF-induced Stat5 activation are regulated by two distinct mechanisms. (PMID:16033816)
• crystal structure of the signaling complex between human granulocyte colony-stimulating factor (GCSF) and a ligand binding region of GCSF receptor (GCSF-R), has been determined to 2.8 A resolution (PMID:16492764)
• Deleterious G-CSFR-mediated signaling events, such as aberrant Stat3 activation demonstrated in a subset of acute myeloid leukemia (AML) patients with poor prognosis, could be exploited for the treatment of AML patients. (PMID:16493051)
• CSF3R nonsense mutations (10 new) in SCN at 17 sites lead to a loss Tyr residues in the intracellular domain of the receptor. CSF3R mutation is an early event in leukemogenesis that has to be accompanied by as yet undefined cooperating molecular events (PMID:16985178)
• single-nucleotide polymorphism (Glu785Lys) is associated with myelodysplastic syndromes and acute myeloid leukemia with multlineage dysplasia (PMID:17024119)
• The observed up-regulation of G-CSF receptors towards a role in the pathophysiology of human ischemic stroke. (PMID:17047971)
• that mutations of CSF3R may provide the “activated tyrosine kinase signal” that is thought to be important for leukemogenesis. (PMID:17494858)
• The G-CSF/G-CSFR autocrine/paracrine signaling loop significantly promotes survival and growth of bladder cancer cells. (PMID:17572226)
• REVIEW: Congenital neutropenia patients with acquired CSF3R mutations define a group with high risk for development of leukemia; discussion of possible pathomechanism (PMID:18536571)
• results indicate ubiquitination required for regulation of G-CSFR-mediated proliferation & cell survival; mutation disrupting G-CSFR ubiquitination induce aberrant signaling & proliferative response to G-CSF; this may contribute to leukemic transformation (PMID:18923646)
• There was no significant difference in expression rate of G-CSFR on CD34+ cells between aplastic anemia, myelodysplastic syndrome, and controls. (PMID:19099633)
• Data show that a lysine within the membrane-proximal region of the granulocyte colony-stimulating factor receptor is indispensable for ubiquitination and lysosomal sorting of the receptor. (PMID:19453968)
• identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain. (PMID:19620628)
• Two cases of X-linked neutropenia are reported that evolved to acute myeloid leukemia or myelodysplasia, with acquisition of G-CSF receptor mutations. (PMID:19794089)
• RAS and CSF3R mutations in severe congenital neutropenia. (PMID:19833857)
• a possible role of G-CSF in malignant transformation, particularly in patients with neutropenia harboring mutations in the gene encoding the G-CSF receptor. (PMID:20237318)
• G-CSF-induced upregulation of MT1-MMP in hematopoietic cells and its enhanced incorporation into membrane lipid rafts contributes to proMMP-2 activation, which facilitates mobilization of HSPC. (PMID:20471446)
• Transgenic Fn14/TWEAK receptor pathway in a mouse model is adversely involved in inflammatory and ischemic brain disease associated with the strongest increase of the endogenous neuroprotective G-CSF and the G-CSF receptor system. (PMID:20557950)
• The results reported in this study suggest a role for CSF3R in the determination of bone density in women. (PMID:20654748)
• Data from rna interference of G-CSFR messenger RNA demonstrated the limited specificity of antibodies for HuG-CSFR expressed on the cell surface. (PMID:20696205)
• CD123+CD34+CD38- cells exhibited lower expression of G-CSF receptors, which might partly explain why MDS clone responds worse to G-CSF in vitro and in vivo. (PMID:20819538)
• Gemcitabine can enhance in vitro the expression rate of bone marrow G-CSFR in chronic myeloid leukemia patients at chronic or blastic phases. (PMID:21129254)
• Pretreatment of PMNs with IFN-gamma or G-CSF for a long-time (22 h)induced a significant lower fungal damage against biofilms compared with planktonic cells. (PMID:21641233)
• An acquired CSF3R mutation in an adult chronic idiopathic neutropenia patient who developed acute myeloid leukaemia. (PMID:22146088)
• CSF3R gene polymorphism plays a significant role in hematopoietic stem and progenitor cells for transplantation. (PMID:22796466)
• Certain missense single nucleotide polymorphisms, especially which are placed in the conserved regions of G-CSFR may possess the capacity to influence the response to G-CSF treatment. (PMID:23159284)
• The stimulating factor 3 receptor mutation (CSF3R-T595I) found in acute myeloid leukemia patients was found to have ligand independent activation properties. (PMID:23508011)
• Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (PMID:23656643)
• A subpopulation of GCSFR positive neuroblastoma cells exhibit enhanced tumorigenicity and a stem cell phenotype. (PMID:23687340)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	csf3r	ENSDARG00000045959
mus_musculus	Csf3r	ENSMUSG00000028859
rattus_norvegicus	Csf3r	ENSRNOG00000008759

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Granulocyte colony-stimulating factor receptor — Q99062 (reviewed: Q99062)

All UniProt accessions (5): Q99062, A0A8V8TNA4, A0A8V8TP76, E9PK56, H0YE86

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differentiation and survival of cells along the neutrophilic lineage. In addition it may function in some adhesion or recognition events at the cell surface.

Subunit / interactions. Homodimer. The dimeric receptor binds two CSF3 molecules. Interacts with CEACAM1; down-regulates the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R.

Subcellular location. Secreted Cell membrane.

Tissue specificity. One or several isoforms have been found in myelogenous leukemia cell line KG-1, leukemia U-937 cell line, in bone marrow cells, placenta, and peripheral blood granulocytes. Isoform GCSFR-2 is found only in leukemia U-937 cells. Isoform GCSFR-3 is highly expressed in placenta.

Post-translational modifications. N-glycosylated.

Disease relevance. Hereditary neutrophilia (NEUTROPHILIA) [MIM:162830] A form of lifelong, persistent neutrophilia, a condition characterized by an increase in the number of neutrophils in the blood. The disease is caused by variants affecting the gene represented in this entry. Neutropenia, severe congenital 7, autosomal recessive (SCN7) [MIM:617014] A form of severe congenital neutropenia, a disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Miscellaneous. Mutations in CSF3R acquired in multipotent hematopoietic progenitor cells and resulting in truncated hyper-responsive forms of the receptor, have been identified in most cases of severe congenital neutropenia (SCN). Patients carrying these mutations are at risk for developing myelodysplastic syndromes and/or acute myeloid leukemia. Constitutive mutations leading to hyporesponsive forms of the receptor are responsible for the refractoriness to CSF3 treatment observed in some SCN patients.

Similarity. Belongs to the type I cytokine receptor family. Type 2 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q99062-1	1, GCSFR-1	yes
Q99062-2	2, GCSFR-2
Q99062-3	3, GCSFR-3
Q99062-4	4, GCSFR-4, D7

RefSeq proteins (3): NP_000751, NP_724781, NP_758519 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003529	Hematopoietin_rcpt_Gp130_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR010457	IgC2-like_lig-bd	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR052672	Type1_Cytokine_Rcpt_Type2	Family

Pfam: PF00041, PF06328

UniProt features (70 total): strand 23, sequence variant 11, glycosylation site 8, disulfide bond 7, domain 6, splice variant 4, helix 3, short sequence motif 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2D9Q	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99062-F1	74.29	0.37

Functional residue map

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

Disulfide bonds (7): 26–52, 46–101, 131–142, 167–218, 177–186, 248–295, 266–309

Glycosylation sites (8): 51, 93, 128, 134, 389, 474, 579, 610

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-449836	Other interleukin signaling
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling

MSigDB gene sets: 310 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOCC_VACUOLAR_MEMBRANE, MODULE_45, MODULE_64, GOCC_CELL_SURFACE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_TAXIS

GO Biological Process (8): defense response (GO:0006952), cell adhesion (GO:0007155), signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), cytokine-mediated signaling pathway (GO:0019221), neutrophil chemotaxis (GO:0030593), regulation of myeloid cell differentiation (GO:0045637), amelogenesis (GO:0097186)

GO Molecular Function (5): cytokine receptor activity (GO:0004896), cytokine binding (GO:0019955), signaling receptor activity (GO:0038023), granulocyte colony-stimulating factor binding (GO:0051916), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), endocytic vesicle membrane (GO:0030666), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by Interleukins	1
Developmental Biology	1
Cytokine Signaling in Immune system	1
Signaling by CSF3 (G-CSF)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cytokine binding	2
cellular anatomical structure	2
response to stress	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
granulocyte chemotaxis	1
neutrophil migration	1
myeloid cell differentiation	1
regulation of hemopoiesis	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
transmembrane signaling receptor activity	1
cytokine-mediated signaling pathway	1
immune receptor activity	1
protein binding	1
molecular transducer activity	1
binding	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
endocytic vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

3273 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSF3R	CSF3	P09919	999
CSF3R	CSF2	P04141	904
CSF3R	JAK2	O60674	888
CSF3R	CEBPA	P49715	862
CSF3R	CSF2RA	P15509	805
CSF3R	IL6R	P08887	789
CSF3R	ELANE	P08246	784
CSF3R	HAX1	O00165	772
CSF3R	CSF1R	P07333	754
CSF3R	EPO	P01588	746
CSF3R	EPOR	P19235	743
CSF3R	STAT3	P40763	741
CSF3R	THPO	P40225	734
CSF3R	KIT	P10721	729
CSF3R	SETBP1	Q9Y6X0	727

IntAct

7 interactions, top by confidence:

A	B	Type	Score
UBC	CSF3R	psi-mi:“MI:0915”(physical association)	0.520
STAT3	CSF3R	psi-mi:“MI:0914”(association)	0.460

BioGRID (35): CSF3R (Reconstituted Complex), CSF3R (Reconstituted Complex), CSF3R (Protein-peptide), CSF3R (Protein-peptide), CSF3R (Negative Genetic), HMGA1 (Negative Genetic), GCK (Negative Genetic), CSF3R (Negative Genetic), DMPK (Negative Genetic), PRKCD (Negative Genetic), SPHK2 (Positive Genetic), CSF3R (Affinity Capture-Western), CSF3R (Affinity Capture-Western), CSF3R (Far Western), CSF3R (Far Western)

ESM2 similar proteins: A0A140LHF2, A0EQL2, D3YZF7, D7PDD4, O15533, O55237, O70394, O70540, O95866, P04278, P05111, P07994, P08689, P0C6B3, P0DP72, P15196, P17490, P18627, P40238, P55101, P60882, P97497, Q00657, Q08351, Q14393, Q14773, Q16671, Q3SWY4, Q5BK54, Q5NKT8, Q5TJE4, Q61790, Q61826, Q62588, Q6PZD2, Q6UVK1, Q6UWB1, Q7Z7M0, Q7Z7M1, Q86VR7

Diamond homologs: P40223, Q99062

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CSF1	up-regulates	CSF3R	binding
CSF2	up-regulates	CSF3R	binding
CSF3	up-regulates	CSF3R	binding
HCK	“up-regulates activity”	CSF3R	phosphorylation

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — AML, BLADDER, HNSC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	14
Uncertain significance	403
Likely benign	248
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070139	NM_000760.4(CSF3R):c.32G>A (p.Trp11Ter)	Pathogenic
1073345	NM_000760.4(CSF3R):c.1388G>A (p.Trp463Ter)	Pathogenic
1322165	NM_000760.4(CSF3R):c.189G>A (p.Trp63Ter)	Pathogenic
1372222	NM_000760.4(CSF3R):c.642_650delinsTTGATCCCATGGATGTTGGTGTCTTGATCCCATGGATGTTG (p.Pro215_Leu217delinsTer)	Pathogenic
1410136	NM_000760.4(CSF3R):c.218dup (p.Arg74fs)	Pathogenic
1416044	NM_000760.4(CSF3R):c.78C>A (p.Cys26Ter)	Pathogenic
1431609	NM_000760.4(CSF3R):c.1525C>T (p.Gln509Ter)	Pathogenic
1453348	NM_000760.4(CSF3R):c.1072-1G>C	Pathogenic
16005	NM_000760.4(CSF3R):c.1919C>A (p.Thr640Asn)	Pathogenic
1981802	NM_000760.4(CSF3R):c.690dup (p.Met231fs)	Pathogenic
1990606	NM_000760.4(CSF3R):c.769C>T (p.Gln257Ter)	Pathogenic
2041994	NM_000760.4(CSF3R):c.1003del (p.Thr335fs)	Pathogenic
242629	NM_000760.4(CSF3R):c.948_963del (p.His317fs)	Pathogenic
242630	NM_000760.4(CSF3R):c.1245del (p.Thr416fs)	Pathogenic
2747049	NM_000760.4(CSF3R):c.1233_1234dup (p.Asn412fs)	Pathogenic
2771578	NM_000760.4(CSF3R):c.1105C>T (p.Gln369Ter)	Pathogenic
2900974	NM_000760.4(CSF3R):c.836G>A (p.Trp279Ter)	Pathogenic
2904711	NM_000760.4(CSF3R):c.1488del (p.Gln498fs)	Pathogenic
3004498	NM_000760.4(CSF3R):c.296_299del (p.Leu99fs)	Pathogenic
3603443	NM_000760.4(CSF3R):c.832_835dup (p.Trp279Ter)	Pathogenic
3663206	NM_000760.4(CSF3R):c.712dup (p.Ser238fs)	Pathogenic
4722821	NM_000760.4(CSF3R):c.1633del (p.Leu545fs)	Pathogenic
4741276	NM_000760.4(CSF3R):c.1318C>T (p.Arg440Ter)	Pathogenic
542855	NM_000760.4(CSF3R):c.1216dup (p.Val406fs)	Pathogenic
542856	NM_000760.4(CSF3R):c.799del (p.Glu267fs)	Pathogenic
649220	NM_000760.4(CSF3R):c.935_963del (p.Arg311_Trp312insTer)	Pathogenic
655386	NM_000760.4(CSF3R):c.203_221del (p.Glu68fs)	Pathogenic
971335	NM_000760.4(CSF3R):c.1404del (p.Ser469fs)	Pathogenic
988352	NM_000760.4(CSF3R):c.2134C>T (p.His712Tyr)	Pathogenic
988435	NM_000760.4(CSF3R):c.2260C>T (p.Gln754Ter)	Pathogenic

SpliceAI

2442 predictions. Top by Δscore:

Variant	Effect	Δscore
1:36467556:A:AC	donor_gain	1.0000
1:36467557:C:CC	donor_gain	1.0000
1:36467647:CCCCT:C	acceptor_gain	1.0000
1:36467648:CCCTC:C	acceptor_gain	1.0000
1:36469256:CT:C	acceptor_gain	1.0000
1:36469258:C:CC	acceptor_gain	1.0000
1:36471451:C:CT	donor_gain	1.0000
1:36471504:T:TA	donor_gain	1.0000
1:36471643:CTGG:C	acceptor_gain	1.0000
1:36472068:T:A	donor_gain	1.0000
1:36481477:CCAG:C	donor_gain	1.0000
1:36467648:CCCT:C	acceptor_gain	0.9900
1:36467649:CCTC:C	acceptor_gain	0.9900
1:36467650:CT:C	acceptor_gain	0.9900
1:36467652:C:CC	acceptor_gain	0.9900
1:36467670:C:CT	acceptor_gain	0.9900
1:36467670:C:T	acceptor_gain	0.9900
1:36467671:G:T	acceptor_gain	0.9900
1:36467816:CCTTA:C	donor_loss	0.9900
1:36467817:CTTAC:C	donor_loss	0.9900
1:36467818:TTAC:T	donor_loss	0.9900
1:36467819:TACCT:T	donor_loss	0.9900
1:36467820:A:AG	donor_loss	0.9900
1:36467821:C:T	donor_loss	0.9900
1:36467921:CA:C	acceptor_gain	0.9900
1:36467922:A:C	acceptor_gain	0.9900
1:36468222:C:CC	acceptor_gain	0.9900
1:36471432:CCT:C	donor_gain	0.9900
1:36471452:C:CT	donor_gain	0.9900
1:36471647:C:CC	acceptor_gain	0.9900

AlphaMissense

5441 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:36473817:C:A	W144C	0.996
1:36473817:C:G	W144C	0.996
1:36472272:C:A	W321C	0.990
1:36472272:C:G	W321C	0.990
1:36472312:C:G	R308P	0.988
1:36473819:A:G	W144R	0.986
1:36473819:A:T	W144R	0.986
1:36475549:C:A	W63C	0.985
1:36475549:C:G	W63C	0.985
1:36468159:A:G	W547R	0.984
1:36468159:A:T	W547R	0.984
1:36472278:G:C	S319R	0.984
1:36472278:G:T	S319R	0.984
1:36472280:T:G	S319R	0.984
1:36473824:C:G	C142S	0.984
1:36473825:A:T	C142S	0.984
1:36472269:G:C	S322R	0.982
1:36472269:G:T	S322R	0.982
1:36472271:T:G	S322R	0.982
1:36473487:A:C	N207K	0.979
1:36473487:A:T	N207K	0.979
1:36472274:A:G	W321R	0.977
1:36472274:A:T	W321R	0.977
1:36468157:C:A	W547C	0.976
1:36468157:C:G	W547C	0.976
1:36475601:C:G	C46S	0.975
1:36475602:A:T	C46S	0.975
1:36472069:C:A	W356C	0.974
1:36472069:C:G	W356C	0.974
1:36472279:C:A	S319I	0.974

dbSNP variants (sampled 300 via entrez): RS1000028486 (1:36483779 T>C), RS1000040823 (1:36480870 A>T), RS1000081865 (1:36483511 G>A,T), RS1000485688 (1:36472497 C>T), RS1000535521 (1:36473210 A>G), RS1000773227 (1:36478108 A>G), RS1000790562 (1:36465679 T>C), RS1000993832 (1:36479794 G>C), RS1001823607 (1:36477589 AAACAAATC>A), RS1001966396 (1:36477819 C>T), RS1001983712 (1:36484423 T>A,C), RS1002261346 (1:36478048 G>A), RS1002549915 (1:36475859 TG>T), RS1002653504 (1:36482254 T>C), RS1002786462 (1:36481048 C>T)

Disease associations

OMIM: gene MIM:138971 | disease phenotypes: MIM:617014, MIM:162830, MIM:202700

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive severe congenital neutropenia due to CSF3R deficiency	Strong	Autosomal recessive
hereditary neutrophilia	Strong	Autosomal dominant

Mondo (4): autosomal recessive severe congenital neutropenia due to CSF3R deficiency (MONDO:0014865), hereditary neutrophilia (MONDO:0008092), severe congenital neutropenia (MONDO:0018542), early T cell progenitor acute lymphoblastic leukemia (MONDO:0100291)

Orphanet (3): Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (Orphanet:420702), Hereditary neutrophilia (Orphanet:279943), Severe congenital neutropenia (Orphanet:42738)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001744	Splenomegaly
HP:0001875	Decreased total neutrophil count
HP:0002719	Recurrent infections
HP:0002863	Myelodysplasia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0008318	Elevated leukocyte alkaline phosphatase
HP:0011463	Childhood onset
HP:0011897	Increased total neutrophil count
HP:0012138	Granulocytic hyperplasia
HP:0033606	Bone marrow maturation arrest

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST004571_24	Iron status biomarkers (total iron binding capacity)	9.000000e-07
GCST004572_5	Iron status biomarkers (transferrin saturation)	9.000000e-07
GCST004608_4	Granulocyte percentage of myeloid white cells	1.000000e-19
GCST004608_5	Granulocyte percentage of myeloid white cells	1.000000e-10
GCST004609_175	Monocyte percentage of white cells	4.000000e-12
GCST004610_79	White blood cell count	3.000000e-31
GCST004610_80	White blood cell count	2.000000e-16
GCST004613_7	Sum neutrophil eosinophil counts	1.000000e-38
GCST004613_8	Sum neutrophil eosinophil counts	2.000000e-21
GCST004614_106	Granulocyte count	6.000000e-38
GCST004614_107	Granulocyte count	2.000000e-21
GCST004620_107	Sum basophil neutrophil counts	7.000000e-39
GCST004620_108	Sum basophil neutrophil counts	1.000000e-21
GCST004626_53	Myeloid white cell count	1.000000e-36
GCST004626_54	Myeloid white cell count	2.000000e-20
GCST004629_3	Neutrophil count	2.000000e-39
GCST004629_4	Neutrophil count	1.000000e-21
GCST004632_84	Lymphocyte percentage of white cells	2.000000e-17
GCST004632_85	Lymphocyte percentage of white cells	3.000000e-13
GCST004633_130	Neutrophil percentage of white cells	1.000000e-23
GCST004633_131	Neutrophil percentage of white cells	1.000000e-14
GCST005973_19	White blood cell count	5.000000e-17
GCST007007_1	Cerebrospinal fluid t-tau levels	2.000000e-06
GCST007008_1	Cerebrospinal fluid p-tau levels	5.000000e-07
GCST009391_1944	Metabolite levels	1.000000e-06
GCST90002379_4	Basophil count	1.000000e-11
GCST90002382_69	Eosinophil percentage of white cells	5.000000e-12
GCST90002389_83	Lymphocyte percentage of white cells	5.000000e-40
GCST90002389_84	Lymphocyte percentage of white cells	5.000000e-12
GCST90002394_133	Monocyte percentage of white cells	1.000000e-21

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0006334	total iron binding capacity
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004760	t-tau measurement
EFO:0004763	p-tau measurement
EFO:0010462	aspartate measurement
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563010	Neutrophilia, Hereditary (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1996 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 2 curated evidence items; also 2 diagnostic, 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
CSF3R T618I	Ruxolitinib	Chronic Neutrophilic Leukemia	Sensitivity/Response	CIViC C	EID6381 +1

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Prolactin receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
anumigilimab	Binding	8.85	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases reaction, increases expression	5
Air Pollutants	affects expression, increases abundance, decreases expression, increases expression	3
Acetaminophen	decreases expression, increases expression	2
Valproic Acid	increases expression, increases methylation	2
triphenyl phosphate	affects expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
cypermethrin	decreases reaction, increases expression	1
3-phenoxybenzoic acid	decreases reaction, increases expression	1
tetrathiomolybdate	increases expression	1
indirubin	increases expression	1
nickel sulfate	increases expression	1
triphenyltin	increases expression	1
fluorotelomer alcohols	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Arsenates	increases expression, affects cotreatment	1
Aspirin	decreases expression	1
Atrazine	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression	1
Cisplatin	decreases expression	1
Coal	increases abundance, increases expression	1
Methotrexate	decreases expression	1
Mustard Gas	decreases expression	1
Naled	affects expression	1
Ozone	affects expression, increases abundance	1
Paraquat	decreases expression	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1069757	Binding	Binding affinity to granulocyte colony stimulating factor receptor by SPR biosensor technique	Molecular design of small organic molecules based on structural information for a conformationally constrained peptide that binds to G-CSF receptor. — Bioorg Med Chem Lett

Cellosaurus cell lines

13 cell lines: 8 factor-dependent cell line, 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1236	GR-ST	Cancer cell line	Male
CVCL_A0UA	32D/G-CSF-R	Factor-dependent cell line	Male
CVCL_A0UB	32D/G-CSF-R p.Gln741Ter	Factor-dependent cell line	Male
CVCL_A0UC	32D/G-CSF-R p.Gln754Ter	Factor-dependent cell line	Male
CVCL_A0UD	32D/G-CSF-R p.Gln739Ter	Factor-dependent cell line	Male
CVCL_A0UE	32D/G-CSF-R p.Tyr727Phe	Factor-dependent cell line	Male
CVCL_A0UF	32D/G-CSF-R p.Tyr752Phe	Factor-dependent cell line	Male
CVCL_A0UG	32D/G-CSF-R p.Tyr767Phe	Factor-dependent cell line	Male
CVCL_A0UH	32D/G-CSF-R p.Tyr787Phe	Factor-dependent cell line	Male
CVCL_A8QX	MDS-L/GR-GFP-N	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01859637	PHASE4	TERMINATED	Immunogenicity, Safety, and Efficacy of Zarzio®/Filgrastim HEXAL® in Patients With Severe Chronic Neutropenia
NCT06361329	PHASE3	RECRUITING	Comparing the Efficacy of VHAG and Traditional Chemotherapy Regimens in Newly Diagnosed ETP-ALL
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00909584	PHASE2	TERMINATED	Study of Ezatiostat (Telintra Tablets) for Treatment of Severe Chronic Neutropenia
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
NCT07012447	PHASE2	RECRUITING	Venetoclax + Azacytidine for Newly Diagnosed ETP-like ALL and T-ALL With Myeloid Mutations
NCT00295971	PHASE1	COMPLETED	Donor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT04582487	Not specified	UNKNOWN	Advancing Chemical and Genomic Strategies for Relapsed/Refractory T-ALL and ETP-ALL