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): 668 total — 16 pathogenic, 5 likely-pathogenic (top 5% of genes corpus-wide)
• GTEx eGene: eQTL in 28 tissues, sQTL in 10 (q < 0.05)
• Phenotypes (HPO): 22
• Drug target: yes — 2 via a complex or family
• Approved drugs acting on a complex or family including it: 1 — Sargramostim (Granulocyte-macrophage colony-stimulating factor receptor)
• 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: 41 — 29 protein_coding, 6 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay

MANE Select: ENST00000381529

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 8, TSL 2: 4, TSL 5: 5

ENST00000381529, ENST00000355432, ENST00000355805, ENST00000381500, ENST00000381509, ENST00000381524, 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, ENST00001046432, ENST00001046433, ENST00001046434, ENST00001046435, ENST00001123398, ENST00001123399, ENST00001133948

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.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.1066 / max 257.7755, expressed in 152 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, blood, granulocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CSF2RA is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 28 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	1.2e-128	+1.17	X:1303975:G:A
Adipose Subcutaneous	eqtl	3.1e-90	+0.72	X:1270360:C:T
Adipose Visceral Omentum	eqtl	5.4e-72	+0.70	X:1270360:C:T
Lung	sqtl	9.8e-49	+0.91	X:1303975:G:A
Breast Mammary Tissue	eqtl	2.7e-29	+0.55	X:1270168:A:T
Nerve Tibial	sqtl	2.1e-22	+0.61	X:1303975:G:A
Adipose Visceral Omentum	sqtl	1.5e-19	+0.58	X:1303975:G:A
Spleen	sqtl	2.9e-18	+1.01	X:1303975:G:A
Adipose Subcutaneous	sqtl	1.8e-15	+0.41	X:1303975:G:A
Thyroid	eqtl	3.2e-14	-0.60	X:1273829:G:A
Esophagus Mucosa	eqtl	6.5e-14	-0.52	X:1269509:C:G
Skin Sun Exposed Lower leg	eqtl	2.3e-09	-0.48	X:1269509:C:G
Breast Mammary Tissue	sqtl	1.2e-07	+0.47	X:1303975:G:A
Nerve Tibial	eqtl	1.4e-07	-0.23	X:1278481:T:G
Whole Blood	eqtl	1.9e-06	-0.09	X:1279119:G:A
Minor Salivary Gland	eqtl	2.0e-05	-0.59	X:1263241:A:C
Brain Hippocampus	eqtl	3.1e-05	+1.15	X:1553822:A:C
Skin Not Sun Exposed Suprapubic	eqtl	3.3e-05	-0.21	X:1270168:A:C
Liver	eqtl	3.8e-04	-0.51	X:1270685:A:G
Heart Atrial Appendage	eqtl	9.5e-04	-0.20	X:1270168:A:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
195321	1.5715	150
195322	0.4759	91
195320	0.0592	36

Top tissues by expression

showing 100 of 278 tissues 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
colonic epithelium	UBERON:0000397	76.94	gold quality
right coronary artery	UBERON:0001625	76.41	gold quality
calcaneal tendon	UBERON:0003701	76.22	gold quality
descending thoracic aorta	UBERON:0002345	76.09	gold quality
lung	UBERON:0002048	76.02	gold quality
diaphragm	UBERON:0001103	75.64	gold quality
thoracic aorta	UBERON:0001515	74.35	gold quality
ascending aorta	UBERON:0001496	74.19	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.95	gold quality
left coronary artery	UBERON:0001626	73.94	gold quality
corpus callosum	UBERON:0002336	73.93	gold quality
minor salivary gland	UBERON:0001830	73.90	gold quality
substantia nigra	UBERON:0002038	73.48	gold quality
mucosa of transverse colon	UBERON:0004991	73.48	gold quality
left uterine tube	UBERON:0001303	73.37	gold quality
type B pancreatic cell	CL:0000169	73.19	gold quality
left adrenal gland	UBERON:0001234	73.13	gold quality
right adrenal gland cortex	UBERON:0035827	73.00	gold quality
left adrenal gland cortex	UBERON:0035825	72.97	gold quality
coronary artery	UBERON:0001621	72.73	gold quality
small intestine	UBERON:0002108	72.56	gold quality
tonsil	UBERON:0002372	72.18	gold quality
saliva-secreting gland	UBERON:0001044	72.04	gold quality
olfactory bulb	UBERON:0002264	71.86	gold quality
amniotic fluid	UBERON:0000173	71.73	gold quality
amygdala	UBERON:0001876	71.69	gold quality
aorta	UBERON:0000947	71.68	gold quality
right adrenal gland	UBERON:0001233	71.65	gold quality
adrenal cortex	UBERON:0001235	71.51	gold quality
adrenal gland	UBERON:0002369	71.50	gold quality
hypothalamus	UBERON:0001898	71.49	gold quality
skin of abdomen	UBERON:0001416	71.47	gold quality
midbrain	UBERON:0001891	71.44	gold quality
skin of leg	UBERON:0001511	71.39	gold quality
transverse colon	UBERON:0001157	70.95	gold quality
mouth mucosa	UBERON:0003729	70.87	gold quality
trabecular bone tissue	UBERON:0002483	70.51	gold quality
caudate nucleus	UBERON:0001873	70.45	gold quality
decidua	UBERON:0002450	70.43	silver quality
palpebral conjunctiva	UBERON:0001812	70.36	gold quality
intestine	UBERON:0000160	70.04	gold quality
right atrium auricular region	UBERON:0006631	70.02	gold quality
tibial artery	UBERON:0007610	69.93	gold quality
multicellular organism	UBERON:0000468	69.90	gold quality
popliteal artery	UBERON:0002250	69.88	gold quality
material anatomical entity	UBERON:0000465	69.87	gold quality
muscle layer of sigmoid colon	UBERON:0035805	69.86	gold quality
anatomical system	UBERON:0000467	69.74	gold quality
zone of skin	UBERON:0000014	69.70	gold quality
esophagus mucosa	UBERON:0002469	69.69	gold quality
cingulate cortex	UBERON:0003027	69.64	gold quality
colon	UBERON:0001155	69.60	gold quality
mucosa of stomach	UBERON:0001199	69.43	gold quality
anterior cingulate cortex	UBERON:0009835	69.38	gold quality
large intestine	UBERON:0000059	69.27	gold quality
metanephros cortex	UBERON:0010533	69.17	gold quality
urinary bladder	UBERON:0001255	69.04	gold quality
putamen	UBERON:0001874	69.00	gold quality
prefrontal cortex	UBERON:0000451	68.93	gold quality
nucleus accumbens	UBERON:0001882	68.88	gold quality
tendon	UBERON:0000043	68.86	gold quality
esophagus	UBERON:0001043	68.72	gold quality
cardiac atrium	UBERON:0002081	68.46	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.32	gold quality
right uterine tube	UBERON:0001302	68.26	gold quality
endocervix	UBERON:0000458	68.24	gold quality
sigmoid colon	UBERON:0001159	67.81	gold quality
Brodmann (1909) area 9	UBERON:0013540	67.70	gold quality
heart	UBERON:0000948	67.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	67.46	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 69 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Placenta	tissue	59.9
Appendix	tissue	22.4
Tonsil	tissue	21.4
Lymph node	tissue	19.2
Bone marrow	tissue	17.2
Medulla oblongata	tissue	16.5
Spinal cord	tissue	14.7
Spleen	tissue	13.5
Substantia nigra	tissue	13.4
Lung	tissue	13.0
Urinary bladder	tissue	11.6
Gallbladder	tissue	11.5
Choroid plexus	tissue	10.6
Locus coeruleus	tissue	9.5
Adipose tissue	tissue	9.1
Hippocampus	tissue	8.9
Thymus	tissue	8.6
Retrosplenial cortex	tissue	8.4
Nucleus accumbens	tissue	7.6
Putamen	tissue	7.2
Rectum	tissue	6.7
Smooth muscle	tissue	6.5
Breast	tissue	6.1
Small intestine	tissue	6.0
Duodenum	tissue	5.5
Colon	tissue	5.3
Adrenal gland	tissue	5.1
Cervix	tissue	4.7
Stomach 1	tissue	4.6
Esophagus	tissue	4.5
Liver	tissue	4.0
Postcentral gyrus	tissue	4.0
Skin 1	tissue	3.9
Fallopian tube	tissue	3.7
Pancreas	tissue	3.2
Parathyroid gland	tissue	2.8
Seminal vesicle	tissue	2.7
Salivary gland	tissue	2.5
Endometrium 1	tissue	2.4
Prostate	tissue	2.3
Heart muscle	tissue	2.2
Kidney	tissue	2.0
Tongue	tissue	1.8
Epididymis	tissue	1.6
Ovary	tissue	1.4
Vagina	tissue	1.4
Thyroid gland	tissue	1.4
Pituitary gland	tissue	1.3
Amygdala	tissue	1.3
Testis	tissue	1.0
Cerebral cortex	tissue	0.9
Retrosplenial and cingulate cortex	tissue	0.9
Basal ganglia	tissue	0.8
Ventral forebrain	tissue	0.8
Somatosensory cortex	tissue	0.8
Retina	tissue	0.7
Skeletal muscle	tissue	0.7
Corpus callosum	tissue	0.7
Olfactory bulb	tissue	0.7
Occipital cortex	tissue	0.7

Brain sub-regions (HPA Brain Atlas): detected in 185; highest nTPM — Lateral funiculus (white matter) (22.4), Medial olivary nucleus (16.5), Nucleus raphe pallidus (16.5), Nucleus rhomboideus (16.5), Anterior funiculus (white matter) (16.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, SPI1

miRNA regulators (miRDB)

Targeting CSF2RA by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

18 miRNAs:

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

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000381529 — one region, missense o/e 1.06. 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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1339754) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired macrophage phagocytosis	1
lung inflammation	1
increased cholesterol level	1
increased lymphocyte cell number	1
abnormal alveolar macrophage morphology	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
IL3RA	protein-coding	3563
CRLF2	protein-coding	64109
MIR3690	ncRNA	100500894
SLC25A6	protein-coding	293
LINC00106	ncRNA	751580
P2RY8	protein-coding	286530
ASMTL-AS1	ncRNA	80161
ASMTL	protein-coding	8623

Protein

Protein identifiers

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

Alternative names: CDw116

All UniProt accessions (8): A0A8Q3SIC6, A0ABB0MVM9, A0ABB0MVN9, A0ABB0MVP0, F2Z3C9, J3JS74, P15509, 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 (59 total): strand 20, glycosylation site 11, splice variant 10, helix 5, disulfide bond 2, topological domain 2, turn 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
4RS1	Crystal structure of receptor-cytokine complex	X-RAY DIFFRACTION	2.68
4NKQ	Structure of a Cytokine Receptor Complex	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Predicted secreted proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, FDA approved drug targets, Biotech drugs, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

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)

Type	Positions
Disulfide bond	126–136, 165–178

Glycosylation sites (11)

Type	Positions
N-linked (glcnac…) asparagine	99, 123, 135, 182, 195, 223, 229, 272, 305, 46, 54

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 17; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

17 pathways:

ID	Pathway	Evidence
R-HSA-5688890	Defective CSF2RA causes SMDP4 ⚕	curated
R-HSA-5688849	Defective CSF2RB causes SMDP5 ⚕	curated
R-HSA-912526	Interleukin receptor SHC signaling	curated
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling	curated
R-HSA-5673001	RAF/MAP kinase cascade	curated
R-HSA-5683826	Surfactant metabolism	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5687613	Diseases associated with surfactant metabolism ⚕	—
R-HSA-5668914	Diseases of metabolism ⚕	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—
R-HSA-451927	Interleukin-2 family signaling	—
R-HSA-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-162582	Signal Transduction	—
R-HSA-449147	Signaling by Interleukins	—

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 (6): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), growth hormone receptor complex (GO:0070195), membrane (GO:0016020)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Signaling by Interleukins	2
Diseases associated with surfactant metabolism	2
MAPK1/MAPK3 signaling	1
Metabolism of proteins	1
Interleukin-2 family signaling	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Immune System	1
Cytokine Signaling in Immune system	1
Disease	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of metabolism	1

GO top-level categories

32 GO namespaces:

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
signaling receptor complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway via JAK-STAT	BP	direct assay
granulocyte-macrophage colony-stimulating factor signaling pathway	BP	direct assay
positive regulation of leukocyte proliferation	BP	direct assay

Protein interactions and networks

STRING

showing 15 of 1,079 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSF2RA	CSF2RB	P32927	947
CSF2RA	CSF2	P04141	905
CSF2RA	SFTPB	P07988	821
CSF2RA	ABCA3	Q99758	820
CSF2RA	SLC25A6	P12236	803
CSF2RA	CSF3R	Q99062	794
CSF2RA	IL3	P08700	765
CSF2RA	CD99	P14209	733
CSF2RA	ASMT	P46597	733
CSF2RA	SHOX	O15266	729
CSF2RA	CSF1R	P07333	697
CSF2RA	IL5	P05113	630
CSF2RA	ITGAM	P11215	609
CSF2RA	CSF3	P09919	605
CSF2RA	STS	P08842	573

IntAct

Human interaction partners of CSF2RA in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
FATE1	physical association	0.560	3
CSF2	physical association	0.400	1
PIK3R1	physical association	0.400	1
IKBKB	proximity	0.270	1
KIT	proximity	0.270	1

BioGRID (12 interactions; top human partners by supporting records): IKBKB (Co-localization; 4 records), CSF2 (Reconstituted Complex), FATE1 (Two-hybrid), FLT3 (Positive Genetic), IL1R1 (Affinity Capture-Western), KIT (Co-localization), PIK3R1 (Affinity Capture-Western), POLI (Reconstituted Complex), SDC2 (Affinity Capture-Western)

SIGNOR signaling

showing 9 of 10 signaling 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

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ GM-CSF receptor-CSF2 complex	3	CSF2RB, CSF2, CSF2RA

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CSF2RB;CSF2RA		Signaling by Colony-Stimulating factor

Disease & clinical

Genetic variants

Variant evidence for CSF2RA: 668 ClinVar records (21 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	5
Uncertain significance	148
Likely benign	213
Benign	86

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 21 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
847249	NM_172245.4(CSF2RA):c.610C>T (p.Gln204Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
856809	NM_172245.4(CSF2RA):c.595C>T (p.Arg199Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
10355	NM_172245.4(CSF2RA):c.586G>A (p.Gly196Arg)	Pathogenic	criteria provided, single submitter	2
839421	NM_172245.4(CSF2RA):c.368_377del (p.Asn123fs)	Pathogenic	criteria provided, single submitter	1
1070210	NM_172245.4(CSF2RA):c.140dup (p.Leu47fs)	Pathogenic	criteria provided, single submitter	1
1074981	NM_172245.4(CSF2RA):c.82C>T (p.Arg28Ter)	Pathogenic	criteria provided, single submitter	1
1075180	NM_172245.4(CSF2RA):c.547del (p.Leu183fs)	Pathogenic	criteria provided, single submitter	1
1433550	NM_172245.4(CSF2RA):c.917G>A (p.Trp306Ter)	Pathogenic	criteria provided, single submitter	1
1451266	NM_172245.4(CSF2RA):c.414G>A (p.Trp138Ter)	Pathogenic	criteria provided, single submitter	1
1685679	NM_172245.4(CSF2RA):c.920_921dup (p.Ser308fs)	Pathogenic	criteria provided, single submitter	1
2062607	NM_172245.4(CSF2RA):c.341C>G (p.Ser114Ter)	Pathogenic	criteria provided, single submitter	1
2088110	NM_172245.4(CSF2RA):c.350_353del (p.Glu117fs)	Pathogenic	criteria provided, single submitter	1
2785274	NM_172245.4(CSF2RA):c.669dup (p.Val224fs)	Pathogenic	criteria provided, single submitter	1
2805729	NM_172245.4(CSF2RA):c.147G>A (p.Trp49Ter)	Pathogenic	criteria provided, single submitter	1
2817095	NM_172245.4(CSF2RA):c.865del (p.Arg289fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CSF2RA’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 1,108):

Position(s)	Effect	Δscore	Sites
X:1300488	acceptor_gain	1.0000
X:1305444–1305445	acceptor_loss	1.0000	5
X:1305445	acceptor_gain	1.0000
X:1268880–1268881	donor_loss	0.9900	4
X:1268885	donor_gain	0.9900
X:1282676–1282677	acceptor_loss	0.9900	6
X:1282780–1282781	donor_loss	0.9900	4
X:1285921–1285922	donor_loss	0.9900	5
X:1288510	acceptor_gain	0.9900
X:1288517	acceptor_loss	0.9900

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.000175
Rectum Adenocarcinoma (validation)	favorable	0.000357
Head and Neck Squamous Cell Carcinoma (TCGA)	favorable	0.0008

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
surfactant metabolism dysfunction, pulmonary, 4	Definitive	Autosomal recessive	2
hereditary pulmonary alveolar proteinosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
COVID-19 research	green
Childhood interstitial lung disease	green
Familial pulmonary fibrosis	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Pulmonary Fibrosis, Familial	green

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 phenotypes (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:

Study	Trait	p-value
GCST011878_3	Mitochondrial heteroplasmy measurement	8e-16
GCST000016_1	Schizophrenia	4e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0600008	mitochondrial heteroplasmy measurement

MeSH disease descriptors

2 disease descriptors:

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)

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes CSF2RA — the drug acts on the assembly or class, not necessarily on this subunit alone.

2 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
SARGRAMOSTIM	Granulocyte-macrophage colony-stimulating factor receptor	2	4
MAVRILIMUMAB	Granulocyte-macrophage colony-stimulating factor receptor	2	2

PharmGKB: 1 entry (CPIC guideline: no)

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	increases expression, affects cotreatment	4
mercuric bromide	increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Nickel	increases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment	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	increases expression, affects cotreatment	1
(+)-JQ1 compound	affects binding, decreases reaction, increases reaction, increases expression	1
Sunitinib	decreases expression	1
Panobinostat	affects cotreatment, increases expression	1
Aldehydes	increases expression	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	increases expression	1
Environmental Pollutants	affects expression	1
Estradiol	increases expression, affects cotreatment	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

2 trials:

NCT	Phase	Status	Title
NCT01511068	Phase 2	COMPLETED	Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)
NCT05761899	Phase 1/2	RECRUITING	Safety and Efficacy of PMT Therapy of hPAP