CSF2RA
protein-codingcolony stimulating factor 2 receptor subunit alpha, the group of Pseudoautosomal region 1|CD molecules
Gene summary
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. [provided by RefSeq, Jul 2008]
- CSF2R
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~56.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010424
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010424
Submitter: ClinGen
Colony-stimulating factor 2 receptor alpha (CSF2RA) was first reported in relation to pseudoautosomal recessive pulmonary alveolar proteinosis simultaneously by two research groups in 2008 (Martinez-Moczygemba et al., PMID: 18955567; Suzuki et. al., PMID: 18955570). *CSF2RA* is located in the pseudoautosomal region (PAR1) of the X and Y chromosomes and is associated with either biallelic or hemizygous (Turner syndrome) variation. *CSF2RA* is part of the receptor complex for the granulocyte-macrophage colony-stimulating factor (GM-CSF) which is involved in the signaling pathway responsible for alveolar macrophage development and function (PMID: 26324812). Alveolar macrophages are responsible for immune response, clearing debris, and surfactant turnover in the lungs. The accumulation of debris and lack of surfactant turnover leads to pulmonary alveolar proteinosis (PAP). PAP can develop as a result of autoantibodies to GM-CSF (>90% of cases) or to germline variation in the GM-CSF receptor complex. Characteristic features of disease can include but are not limited to: milky bronchoalveolar lavage fluid, crazy-paving pattern on radiograph, enlarged and foamy appearing macrophages, dyspnea, respiratory insufficiency, or cyanosis (PMID: 30846703). Age of onset for hereditary forms of PAP is apparently highly variable with a majority of cases in this curation presenting in late infancy or childhood. Six variants (missense, nonsense, canonical splice site, and frameshift deletion) that have been reported in six probands in 2 publications (PMIDs 20622029, 25425184) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a mouse model that nearly fully recapitulates the human patient phenotype, expression studies, and rescue of function in patient iPSC cells transfected with wildtype *CSF2RA* (PMIDs: 20622029, 26484569, 35043685, 24279725). In summary, there is definitive evidence supporting the relationship between *CSF2RA* and pseudoautosomal recessive pulmonary alveolar proteinosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date September 16, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0012580
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Pulmonary
Intervention: Pulmonary
Rationale: The condition manifests with childhood-onset respiratory insufficiency due to pulmonary alveolar proteinosis , and treatment with whole-lung lavage has been reported as beneficial; It has additionally been reported that diagnosis has important therapeutic implications, as BMT/HSCT can be effective
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CSF2RA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript . Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 69 | 8 | 79 | ||
| missense | 1 | 1 | 136 | 15 | 12 | 165 |
| nonsense | 8 | 1 | 1 | 10 | ||
| start loss | 0 | |||||
| frameshift | 7 | 7 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 16 | 5 | 138 | 85 | 20 | 264 |
Highest pathogenic variant AF is 0.0000199667
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| Ensembl | ENSP00000370940.3 | 11 | MANE Select | |
| RefSeq | NP_001155001.1 | 22 | Standard | |
| RefSeq | NP_001155002.1 | 24 | Standard | |
| RefSeq | NP_001155003.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Hematopoietic cell lineage - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- JAK-STAT-Core
Biological Process
- MAPK cascade
- peptidyl-tyrosine phosphorylation
- cytokine-mediated signaling pathway
- cellular protein metabolic process
Molecular Function
- protein tyrosine kinase activity
- cytokine receptor activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
- cytokine binding
Cellular Component
- extracellular region
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
- receptor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000417535
- Coding exons
- 12
- Length
- 41582
- Individuals with no LoFs
- 124800
- Homozygous LoFs
- 18
- Heterozygous LoFs
- 773
- Defined
- 125591
- p
- 0.00315
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.837 | 260 | 225 | 1.16 | 0.0000148 | 2826 |
| Missense (PolyPhen) | 74 | 66.05 | 1.1204 | 871 | ||
| Synonymous | -3.40 | 133 | 91.6 | 1.45 | 0.00000680 | 816 |
| Loss of Function | 1.11 | 18 | 23.9 | 0.754 | 0.00000146 | 278 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.041 | 0.041 | notable |
| Latino/Admixed American | 0.0026 | 0.0025 | notable |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00026 | 0.00026 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00082 | 0.00082 | rare |
dbNSFP Gene Annotations
Source:
- Function
- 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.;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:18955567, ECO:0000269|PubMed:18955570}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0175
- RVIS EVS
- 1
- RVIS percentile EVS
- 90.77
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.820
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |