CSF2RA

Summary

CSF2RA (colony stimulating factor 2 receptor subunit alpha, HGNC:2435) is a protein-coding gene on chromosome Xp22.32 and Yp11.3, encoding Granulocyte-macrophage colony-stimulating factor receptor subunit alpha (P15509). Low affinity receptor for granulocyte-macrophage colony-stimulating factor.

The protein encoded by this gene is the alpha subunit of the heterodimeric receptor for colony stimulating factor 2, a cytokine which controls the production, differentiation, and function of granulocytes and macrophages. The encoded protein is a member of the cytokine family of receptors. This gene is found in the pseudoautosomal region (PAR) of the X and Y chromosomes. Multiple transcript variants encoding different isoforms have been found for this gene, with some of the isoforms being membrane-bound and others being soluble.

Source: NCBI Gene 1438 — RefSeq curated summary.

At a glance

• Gene–disease (curated): surfactant metabolism dysfunction, pulmonary, 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 649 total — 17 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_172245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2435
Approved symbol	CSF2RA
Name	colony stimulating factor 2 receptor subunit alpha
Location	Xp22.32 and Yp11.3
Locus type	gene with protein product
Status	Approved
Aliases	CD116, alphaGMR
Ensembl gene	ENSG00000198223
Ensembl biotype	protein_coding
OMIM	306250, 425000
Entrez	1438

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 26 protein_coding, 6 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000355432, ENST00000355805, ENST00000381500, ENST00000381509, ENST00000381524, ENST00000381529, ENST00000412290, ENST00000432318, ENST00000475259, ENST00000477940, ENST00000478256, ENST00000481245, ENST00000486791, ENST00000491683, ENST00000493312, ENST00000494969, ENST00000498153, ENST00000696230, ENST00000718259, ENST00000718260, ENST00000718261, ENST00000718262, ENST00000886979, ENST00000886980, ENST00000886981, ENST00000886982, ENST00000886983, ENST00000969305, ENST00000969306, ENST00000969307, ENST00000969308, ENST00000969309, ENST00000969310, ENST00000969311

RefSeq mRNA: 25 — MANE Select: NM_172245 NM_001161529, NM_001161530, NM_001161531, NM_001161532, NM_001379153, NM_001379154, NM_001379155, NM_001379156, NM_001379158, NM_001379159, NM_001379160, NM_001379161, NM_001379162, NM_001379163, NM_001379164, NM_001379165, NM_001379166, NM_001379167, NM_001379168, NM_001379169, NM_006140, NM_172245, NM_172246, NM_172247, NM_172249

CCDS: CCDS35190, CCDS35191, CCDS35192, CCDS35193, CCDS55359, CCDS55360

Canonical transcript exons

ENST00000381529 — 13 exons

Exon	Start	End
ENSE00001823875	1268814	1268879
ENSE00003523981	1309402	1309935
ENSE00003531064	1303923	1304019
ENSE00003586821	1294328	1294461
ENSE00003598154	1305446	1305527
ENSE00003653591	1295427	1295456
ENSE00003689612	1300491	1300626
ENSE00003966482	1288759	1288888
ENSE00003966483	1282678	1282779
ENSE00003966484	1290337	1290509
ENSE00003966485	1285778	1285920
ENSE00003966490	1274755	1274818
ENSE00003966491	1288519	1288642

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 97.17.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.17	gold quality
mononuclear cell	CL:0000842	96.30	gold quality
leukocyte	CL:0000738	96.09	gold quality
blood	UBERON:0000178	93.80	gold quality
granulocyte	CL:0000094	92.08	gold quality
placenta	UBERON:0001987	90.53	gold quality
sural nerve	UBERON:0015488	87.53	gold quality
right lung	UBERON:0002167	86.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.06	gold quality
upper lobe of left lung	UBERON:0008952	85.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.47	gold quality
vermiform appendix	UBERON:0001154	85.31	gold quality
gall bladder	UBERON:0002110	85.14	gold quality
bone marrow	UBERON:0002371	84.74	gold quality
bone marrow cell	CL:0002092	84.57	gold quality
spleen	UBERON:0002106	84.07	gold quality
upper lobe of lung	UBERON:0008948	83.93	gold quality
lymph node	UBERON:0000029	82.11	gold quality
spinal cord	UBERON:0002240	81.93	gold quality
omental fat pad	UBERON:0010414	80.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.03	gold quality
peritoneum	UBERON:0002358	80.02	gold quality
caecum	UBERON:0001153	79.77	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.71	gold quality
adipose tissue	UBERON:0001013	79.59	gold quality
rectum	UBERON:0001052	79.44	gold quality
connective tissue	UBERON:0002384	78.90	gold quality
smooth muscle tissue	UBERON:0001135	78.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.48	gold quality
tibial nerve	UBERON:0001323	77.39	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	3625.71
E-MTAB-8498	yes	3374.16
E-GEOD-130473	yes	342.20
E-HCAD-36	yes	245.12
E-MTAB-8142	yes	98.64
E-HCAD-1	yes	50.95
E-MTAB-6678	yes	42.06
E-GEOD-84465	yes	39.73
E-MTAB-6701	yes	37.14
E-CURD-122	yes	23.11
E-CURD-46	yes	19.79
E-HCAD-25	yes	17.43
E-MTAB-8410	yes	14.51
E-CURD-88	yes	12.40
E-MTAB-9067	yes	12.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, SPI1

miRNA regulators (miRDB)

18 targeting CSF2RA, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-376C-3P	97.63	68.88	1263
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-4485-5P	95.91	59.69	198

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 34)

• The cytosolic domain of the hGM Ralpha chain is required for differentiation mediated by activation of the hGM Ralpha, beta(c) receptor complex. (PMID:12384414)
• soluble forms of the GM-CSF receptor alpha chain and beta chain were produced and a novel mechanism of receptor assembly was demonstrated (PMID:12393492)
• Constitutive secretion of soluble GMR alpha by monocytes (but not lymphocytes) is up-regulated by GM-CSF and inflammatory mediators in a protein form that represents a mixed population of alternatively spliced and proteolytically cleaved species. (PMID:12421947)
• Analysis of the 5’ promoter of the GM-CSF receptor alpha gene. (PMID:12504125)
• identified the alpha-chain of the GMCSF receptor as interaction partner of IkappaB kinase beta; direct interaction of IKKbeta and GMRalpha in cells was verified. (PMID:12637324)
• GM-CSF receptors exhibit different modes of signaling in a factor-dependent bipotential myeloid cell line. (PMID:14504109)
• used the intracellular portion of the alpha subunit of the GM-CSF receptor to search for interacting proteins and identified the 67-kDa laminin receptor as a binding partner (PMID:14614142)
• receptors alphaGMR and c-Kit could interact to coordinate their signal initiation; alphaGMR inhibited c-Kit auto-phosphorylation induced by the ligand stem cell factor (PMID:16760463)
• Sequencing of colony stimulating factor, receptor 2 alpha in an independent case-control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. (PMID:17522711)
• The novel GMRalpha transcript identified herein contains a previously undescribed exon of the GMRalpha gene; this exon derives from an Alu DNA repeat element (PMID:17681666)
• Results highlight the importance of GM-CSFR expression in monocytes for cytokine-induced myeloid dendritic cells (DC) generation and point to GM-CSF as a direct player in the generation of functionally distinct DC. (PMID:18236400)
• best diffracting crystals of ternary complex were obtained using the N346Q mutation of the betac subunit. Crystals grew using polyethylene glycol 3350 with a high concentration of proline, belonged to space group P6(3)22 and diffracted to 3.3 A resolution (PMID:18678938)
• Mutagenesis of the GM-CSF receptor at the dodecamer interface and functional studies reveal that dodecamer formation is required for receptor activation and signaling. (PMID:18692472)
• Results suggest that that pulmonary alveolar proteinosis can result from a genetic deficiency of the GM-CSF receptor alpha chain, encoded in the X-chromosome pseudoautosomal region 1. (PMID:18955567)
• These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP. (PMID:18955570)
• The expression rate of GM-CSFR in myelodysplastic syndrome patients was significantly higher than in aplastic anemia patients and controls. (PMID:19099633)
• Data show that Deletion of the Ig-like domain of GM-CSFRalpha abolished direct GM-CSF binding and decreased growth signalling in the presence of hbetac. (PMID:20078425)
• 67-kDa laminin receptor expression influenced the characteristics of leukemia cells toward an aggressive phenotype and increased the number of granulocyte-macrophage colony-stimulating factor receptors (PMID:21056082)
• Identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor. (PMID:21557945)
• The GM-CSF Ralpha were ubiquitously but not uniformly expressed in neurons throughout the brain and downregulation in brain in patient with alzheimenr disease. (PMID:22430742)
• This study reveals a novel functional role of clathrin-coated structure in GMR signaling and the oncogenesis of JAK2V617F. (PMID:22935703)
• Studies indicate the action of GM-CSF can be inhibited by at least two approaches: inhibition by GM-CSF neutralising antibodies, or blockade of GM-CSF binding to its receptor by antibodies against the GM-CSF receptor alpha chain CSF2Ralpha. (PMID:23933508)
• A possible relationship between dysfunction of the granulocyte-macrophage colony stimulating factor receptor, mapping to the pseudoautosomal X-Y region, may exist in myelodysplastic patients with initially lymphocytic Sweet syndrome. (PMID:24714374)
• Our cohort broadens the spectrum of knowledge about the clinical variability and genotype-phenotype correlations of juvenile PAP, and illustrates the favorable outcome of WLL treatment in severely affected patients (PMID:25425184)
• regulatory molecule causative of aortic dissection and intramural haematoma (PMID:25923510)
• Conformational changes in the GM-CSF receptor suggest a molecular mechanism for affinity conversion and receptor signaling. (PMID:27396825)
• Family-based whole genome analysis of a family with hereditary pulmonary alveolar proteinosis revealed a homozygous deletion that disrupts CSF2RA, CRLF2, and IL3RA gene in the pseudoautosomal region of the X chromosome in the affected child and one of asymptomatic siblings. (PMID:28233860)
• lesions from human secondary progressive multiple sclerosis, but not primary progressive multiple sclerosis patients shows extensive recruitment of GM-CSF Ralpha+ myeloid cells (PMID:28641926)
• Missense mutations in CSF2RA gene is associated with Pediatric Crohn’s Disease. (PMID:30124884)
• These data show that loss of membrane GM-CSFRalpha following GM-CSF exposure does not preclude sustained GM-CSF/GM-CSFRalpha signaling and that this receptor plays a key role in ligand clearance. Hence neutrophilic activation via GM-CSFR may play an important role in neutrophilic lung inflammation even in the absence of high GM-CSF levels or GM-CSFRalpha expression. (PMID:30942918)
• Expression of granulocyte macrophage-colony stimulating factor and its receptor in the synovium of osteoarthritis patients is negatively correlated with pain. (PMID:32365364)
• miR-532-3p-CSF2RA Axis as a Key Regulator of Vulnerable Atherosclerotic Plaque Formation. (PMID:32473103)
• CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages. (PMID:35019940)
• A murine model of hereditary pulmonary alveolar proteinosis caused by homozygous Csf2ra gene disruption. (PMID:35043685)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Csf2ra	ENSMUSG00000059326
rattus_norvegicus	Csf2ra	ENSRNOG00000049782

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Granulocyte-macrophage colony-stimulating factor receptor subunit alpha — P15509 (reviewed: P15509)

Alternative names: CDw116

All UniProt accessions (5): A0A8Q3SIC6, P15509, F2Z3C9, J3JS74, V9GYE9

UniProt curated annotations — full annotation on UniProt →

Function. Low affinity receptor for granulocyte-macrophage colony-stimulating factor. Transduces a signal that results in the proliferation, differentiation, and functional activation of hematopoietic cells.

Subunit / interactions. Heterodimer of an alpha and a beta subunit. The beta subunit is common to the IL3, IL5 and GM-CSF receptors. The signaling GM-CSF receptor complex is a dodecamer of two head-to-head hexamers of two alpha, two beta, and two ligand subunits.

Subcellular location. Cell membrane Secreted Secreted Secreted.

Disease relevance. Pulmonary surfactant metabolism dysfunction 4 (SMDP4) [MIM:300770] A rare lung disorder due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress. 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. The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes.

Similarity. Belongs to the type I cytokine receptor family. Type 5 subfamily.

Isoforms (8)

UniProt ID	Names	Canonical?
P15509-1	1	yes
P15509-2	2
P15509-3	3
P15509-4	4
P15509-5	5
P15509-6	6
P15509-7	7, Alu-GMRalpha
P15509-8	8

RefSeq proteins (25): NP_001155001, NP_001155002, NP_001155003, NP_001155004, NP_001366082, NP_001366083, NP_001366084, NP_001366085, NP_001366087, NP_001366088, NP_001366089, NP_001366090, NP_001366091, NP_001366092, NP_001366093, NP_001366094, NP_001366095, NP_001366096, NP_001366097, NP_001366098, NP_006131, NP_758448, NP_758449, NP_758450, NP_758452 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003532	Short_hematopoietin_rcpt_2_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015321	TypeI_recpt_CBD	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR040907	IL3Ra_N	Domain

Pfam: PF09240, PF18611

UniProt features (56 total): strand 20, glycosylation site 11, splice variant 10, disulfide bond 2, topological domain 2, turn 2, helix 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4RS1	X-RAY DIFFRACTION	2.68
4NKQ	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15509-F1	82.15	0.61

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 (2): 126–136, 165–178

Glycosylation sites (11): 99, 123, 135, 182, 195, 223, 229, 272, 305, 46, 54

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683826	Surfactant metabolism
R-HSA-5688849	Defective CSF2RB causes SMDP5
R-HSA-5688890	Defective CSF2RA causes SMDP4
R-HSA-912526	Interleukin receptor SHC signaling

MSigDB gene sets: 272 (showing top): REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, MODULE_64, GOCC_CELL_SURFACE, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, PID_INTEGRIN_A9B1_PATHWAY, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, LINDSTEDT_DENDRITIC_CELL_MATURATION_B, GOBP_LEUKOCYTE_PROLIFERATION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP

GO Biological Process (8): cell surface receptor signaling pathway via JAK-STAT (GO:0007259), positive regulation of cell population proliferation (GO:0008284), cytokine-mediated signaling pathway (GO:0019221), granulocyte-macrophage colony-stimulating factor signaling pathway (GO:0038157), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), growth hormone receptor signaling pathway (GO:0060396), positive regulation of leukocyte proliferation (GO:0070665), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (6): growth hormone receptor activity (GO:0004903), peptide hormone binding (GO:0017046), cytokine binding (GO:0019955), signaling receptor activity (GO:0038023), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), granulocyte macrophage colony-stimulating factor receptor complex (GO:0030526), growth hormone receptor complex (GO:0070195), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Diseases associated with surfactant metabolism	2
Signaling by Interleukins	1
MAPK1/MAPK3 signaling	1
Metabolism of proteins	1
Interleukin-2 family signaling	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytokine-mediated signaling pathway	2
cell surface receptor signaling pathway via STAT	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
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
positive regulation of receptor signaling pathway via STAT	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to growth hormone stimulus	1
positive regulation of cell population proliferation	1
leukocyte proliferation	1
regulation of leukocyte proliferation	1
signal transduction	1
cytokine receptor activity	1
hormone binding	1
protein binding	1
molecular transducer activity	1
transmembrane signaling receptor activity	1
cytokine binding	1
immune receptor activity	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
plasma membrane signaling receptor complex	1
signaling receptor complex	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSF2RA	CSF2	P04141	998
CSF2RA	CSF2RB	P32927	996
CSF2RA	CSF3	P09919	809
CSF2RA	ABCA3	Q99758	809
CSF2RA	CSF3R	Q99062	805
CSF2RA	SLC25A6	P12236	785
CSF2RA	IL3	P08700	783
CSF2RA	SHOX	O15266	745
CSF2RA	CD99	P14209	715
CSF2RA	CSF1R	P07333	695
CSF2RA	ASMT	P46597	692
CSF2RA	SFTPB	P07988	668
CSF2RA	CRLF2	Q9HC73	651
CSF2RA	IL2	P01585	640
CSF2RA	IL5	P05113	639

IntAct

8 interactions, top by confidence:

A	B	Type	Score
FATE1	CSF2RA	psi-mi:“MI:0915”(physical association)	0.560
CSF2RA	FATE1	psi-mi:“MI:0915”(physical association)	0.560
CSF2	CSF2RA	psi-mi:“MI:0915”(physical association)	0.400
PIK3R1	CSF2RA	psi-mi:“MI:0915”(physical association)	0.400
CSF2RA	KIT	psi-mi:“MI:2364”(proximity)	0.270
CSF2RA	IKBKB	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (11): FATE1 (Two-hybrid), CSF2RA (Co-localization), CSF2RA (Co-localization), CSF2RA (Positive Genetic), IL1R1 (Affinity Capture-Western), CSF2RA (Reconstituted Complex), CSF2RA (Affinity Capture-Western), PIK3R1 (Affinity Capture-Western), IKBKB (Two-hybrid), CSF2RA (Reconstituted Complex), CSF2RA (FRET)

ESM2 similar proteins: A0A0E4BZH1, A4KWA1, A5D7V5, A7TZE6, D3W0D1, O35778, O54707, P15509, P27471, P27812, P27814, P78380, P79391, Q0VCS6, Q12918, Q13241, Q28110, Q38HS3, Q49BZ4, Q58DF9, Q5NKN2, Q5NKN4, Q5QGZ9, Q60653, Q60660, Q60682, Q63378, Q64329, Q6QLQ4, Q7YR73, Q80ZC8, Q863H3, Q8BWY2, Q8C567, Q8HZR8, Q8MHY9, Q8NC01, Q8VD98, Q92478, Q99JB4

Diamond homologs: P15509, P26951, Q00941, P26952, P21183, Q01344

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CSF2	“up-regulates activity”	CSF2RA	binding
CSF2RA	“up-regulates activity”	JAK2	binding
JAK2	“up-regulates activity”	CSF2RA	phosphorylation
CSF2RA	“form complex”	CSF2RA/CSF2RB	binding
CSF2RA	up-regulates	STAT5A
CSF2RA	up-regulates	JAK2
CSF2	up-regulates	CSF2RA	binding
CSF1	up-regulates	CSF2RA	binding
CSF3	up-regulates	CSF2RA	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	6
Uncertain significance	147
Likely benign	197
Benign	101

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
10355	NM_172245.4(CSF2RA):c.586G>A (p.Gly196Arg)	Pathogenic
1070210	NM_172245.4(CSF2RA):c.140dup (p.Leu47fs)	Pathogenic
1074981	NM_172245.4(CSF2RA):c.82C>T (p.Arg28Ter)	Pathogenic
1075180	NM_172245.4(CSF2RA):c.547del (p.Leu183fs)	Pathogenic
1433550	NM_172245.4(CSF2RA):c.917G>A (p.Trp306Ter)	Pathogenic
1451266	NM_172245.4(CSF2RA):c.414G>A (p.Trp138Ter)	Pathogenic
1685678	NM_172245.4(CSF2RA):c.649C>T (p.Arg217Ter)	Pathogenic
1685679	NM_172245.4(CSF2RA):c.920_921dup (p.Ser308fs)	Pathogenic
2062607	NM_172245.4(CSF2RA):c.341C>G (p.Ser114Ter)	Pathogenic
2088110	NM_172245.4(CSF2RA):c.350_353del (p.Glu117fs)	Pathogenic
2785274	NM_172245.4(CSF2RA):c.669dup (p.Val224fs)	Pathogenic
2805729	NM_172245.4(CSF2RA):c.147G>A (p.Trp49Ter)	Pathogenic
2817095	NM_172245.4(CSF2RA):c.865del (p.Arg289fs)	Pathogenic
3689735	NM_172245.4(CSF2RA):c.221del (p.Leu74fs)	Pathogenic
839421	NM_172245.4(CSF2RA):c.368_377del (p.Asn123fs)	Pathogenic
847249	NM_172245.4(CSF2RA):c.610C>T (p.Gln204Ter)	Pathogenic
856809	NM_172245.4(CSF2RA):c.595C>T (p.Arg199Ter)	Pathogenic
1473649	NM_172245.4(CSF2RA):c.810+2T>A	Likely pathogenic
1948181	NM_172245.4(CSF2RA):c.647-2A>G	Likely pathogenic
1973069	NM_172245.4(CSF2RA):c.586G>C (p.Gly196Arg)	Likely pathogenic
2189920	NM_172245.4(CSF2RA):c.1043+1G>A	Likely pathogenic
4820183	NC_000023.10:g.1393559_1448559del	Likely pathogenic
4849453	NM_172245.4(CSF2RA):c.220-1G>C	Likely pathogenic

SpliceAI

2202 predictions. Top by Δscore:

Variant	Effect	Δscore
X:1282676:A:AG	acceptor_gain	1.0000
X:1282677:G:GG	acceptor_gain	1.0000
X:1282677:GCT:G	acceptor_gain	1.0000
X:1282677:GCTC:G	acceptor_gain	1.0000
X:1282677:GCTCT:G	acceptor_gain	1.0000
X:1288509:A:AG	acceptor_gain	1.0000
X:1288518:GCTCA:G	acceptor_gain	1.0000
X:1300488:A:G	acceptor_gain	1.0000
X:1300490:GATTA:G	acceptor_gain	1.0000
X:1305438:T:TA	acceptor_gain	1.0000
X:1305444:A:AG	acceptor_gain	1.0000
X:1305444:AG:A	acceptor_gain	1.0000
X:1305445:G:GA	acceptor_gain	1.0000
X:1305445:GG:G	acceptor_gain	1.0000
X:1305445:GGT:G	acceptor_gain	1.0000
X:1305445:GGTT:G	acceptor_gain	1.0000
X:1305517:TGG:T	donor_gain	1.0000
X:1268862:G:GT	donor_gain	0.9900
X:1268876:GGGG:G	donor_gain	0.9900
X:1268877:GGG:G	donor_gain	0.9900
X:1268877:GGGG:G	donor_gain	0.9900
X:1268877:GGGGT:G	donor_loss	0.9900
X:1268878:GG:G	donor_gain	0.9900
X:1268878:GGG:G	donor_gain	0.9900
X:1268878:GGGTA:G	donor_loss	0.9900
X:1268879:GG:G	donor_gain	0.9900
X:1268879:GGT:G	donor_loss	0.9900
X:1268880:G:GC	donor_loss	0.9900
X:1268880:G:GG	donor_gain	0.9900
X:1268881:T:G	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS111065301 (X:1316027 C>A,G), RS111066019 (X:1267234 G>A,C,T), RS111066020 (X:1267366 A>C,G), RS111161730 (X:1268128 C>T), RS111161732 (X:1268216 G>A), RS111161733 (X:1268379 G>A), RS111161734 (X:1268388 A>G), RS111162402 (X:1268167 A>G), RS111162403 (X:1268283 G>A,T), RS111162404 (X:1268289 A>C,G), RS111162405 (X:1268338 G>A), RS111221444 (X:1316011 G>A,T), RS111232301 (X:1294181 C>A,G,T), RS111239872 (X:1311125 T>A,C), RS111276459 (X:1271580 G>A)

Disease associations

OMIM: gene MIM:306250, MIM:425000 | disease phenotypes: MIM:300770

GenCC curated gene-disease

Disease	Classification	Inheritance
surfactant metabolism dysfunction, pulmonary, 4	Definitive	Autosomal recessive
hereditary pulmonary alveolar proteinosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
surfactant metabolism dysfunction, pulmonary, 4	Definitive	AR

Mondo (2): surfactant metabolism dysfunction, pulmonary, 4 (MONDO:0010424), hereditary pulmonary alveolar proteinosis (MONDO:0012580)

Orphanet (1): Hereditary pulmonary alveolar proteinosis (Orphanet:264675)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0001417	X-linked inheritance
HP:0001508	Failure to thrive
HP:0001531	Failure to thrive in infancy
HP:0001649	Tachycardia
HP:0002091	Restrictive ventilatory defect
HP:0002098	Respiratory distress
HP:0002789	Tachypnea
HP:0003651	Foam cells
HP:0004887	Respiratory failure requiring assisted ventilation
HP:0006517	Intraalveolar phospholipid accumulation
HP:0010876	Abnormal circulating protein concentration
HP:0011949	Acute infectious pneumonia
HP:0012418	Hypoxemia
HP:0012735	Cough
HP:0025179	Ground-glass opacification
HP:0025391	Crazy paving pattern
HP:0030057	Autoimmune antibody positivity
HP:0030830	Crackles
HP:0031029	Elevated circulating CEA concentration
HP:0032341	Reduced forced vital capacity
HP:0032342	Reduced forced expiratory volume in one second
HP:0045051	Decreased DLCO

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000016_1	Schizophrenia	4.000000e-07
GCST011878_3	Mitochondrial heteroplasmy measurement	8.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0600008	mitochondrial heteroplasmy measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535832	Pulmonary alveolar proteinosis, congenital (supp.)
C567461	Surfactant Metabolism Dysfunction, Pulmonary, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364169 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — IL-3 receptor family

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

Ligand	Action	Affinity	Parameter
mavrilimumab	Binding	9.86	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
mercuric bromide	increases expression, affects cotreatment	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	affects cotreatment, decreases expression, increases abundance, increases expression	2
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
butyraldehyde	increases expression	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases reaction, increases reaction, increases expression, affects binding	1
Sunitinib	decreases expression	1
Panobinostat	affects cotreatment, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Aldehydes	increases expression	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	increases expression	1
Environmental Pollutants	affects expression	1
Estradiol	affects cotreatment, increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01511068	PHASE2	COMPLETED	Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)
NCT05761899	PHASE1/PHASE2	RECRUITING	Safety and Efficacy of PMT Therapy of hPAP