SOCS1
protein-codingsuppressor of cytokine signaling 1, the group of SH2 domain containing|Suppressors of cytokine signaling
Gene summary
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including IL2, IL3 erythropoietin (EPO), CSF2/GM-CSF, and interferon (IFN)-gamma. The protein encoded by this gene functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. Knockout studies in mice suggested the role of this gene as a modulator of IFN-gamma action, which is required for normal postnatal growth and survival. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0800130
Submitter: ClinGen
*SOCS1* was first reported in relation to autosomal dominant autoinflammatory syndrome with immunodeficiency in 2020 (Thaventhiran et al., PMID: 32499645; Lee et al, PMID: 32853638; Hadjadj et al, PMID 33087723). An autosomal dominant, immune dysregulation disorder with incomplete penetrance characterized by autoimmmunity (autoimmune cytopenia, hemolytic anemia, thrombocytopenia) and lymphoproliferation. Additional variable features may include autoimmune thyroiditis, psoriasis or eczema, nephritis, hepatitis, and symptoms of systemic lupus erythematosus. Immunodeficiency is present in some patients. Disease onset is usually in the first decades of life, although later onset has been reported. Twelve variants (missense, nonsense) that have been reported in probands in five publications (PMIDs: 39840313, 39005503, 33087723, 32853638, 32499645) are included in this curation. *SOCS1* has only one coding exon therefore non-mediated decay is not predicted for any variant. Several probands present with thrombocytopenia, hepatitis, recurrent infections, neutropenia, while others have been diagnosed with common variable immunodeficiency. Because *SOCS1* haploinsufficiency has incomplete penetrance, the phenotypic features of probands, even within the same families, exist on a wide spectrum of severity. This gene-disease relationship is also supported by animal models, functional assays, and protein interactions. Model systems in mice (PMIDs: 10490099, 11371356) *SOCS1* knockout mice exhibit severe inflammation in the neonatal period which includes immune-mediated hepatitis, and thrombocytopenia, features shared by haploinsufficient humans. Injury to the liver is shown in complete *SOCS1* knockout in mice predicts that without cross-talk inhibition via SOCS-1, IL-4 and IFN-γ signaling there is damage to various organs, localized by other factors such as susceptibility to infection. *SOCS1* plays a role in downregulating cytokine signaling by inhibiting the activity of Janus kinases (JAKs), key components of the JAK/STAT signaling pathway. Functional alteration studies (PMID: 34421895) show that when *SOCS1* had reduced protein expression, organ damage through chronic infections and/or autoimmunity is predictive. Meanwhile, increased activity in the FAK – AKT – RS6K pathway may explain the accumulation of autoimmunity. Biochemical function (PMID: 9341160) and protein interactions (PMID: 29674694) further support the role of *SOCS1* to have a function consistent with the immunodeficiency phenotype observed in patients via the regulation of JAK/STAT pathways. In summary, there is definitive evidence supporting the relationship between SOCS1 in relation to autosomal dominant autoinflammatory syndrome with immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen PIRD GCEP on the meeting date February, 18, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0800130
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0800130
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007179
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic
Intervention: Allergy/Immunology/Infectious
Rationale: The condition has been described as involving recurrent infections and autoimmune disorder, and medical management (eg, with steroids, rituximab) has been described as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SOCS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003745.2. 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 | 1 | 6 | 1 | 8 | ||
| missense | 1 | 3 | 66 | 2 | 72 | |
| nonsense | 1 | 3 | 1 | 5 | ||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 3 | 3 | 9 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 5 | 9 | 72 | 8 | 1 | 95 |
Highest pathogenic variant AF is 0.0000022482554
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003736.1 | 1 | MANE Select | |
| Ensembl | ENSP00000329418.2 | 1 | MANE Select | |
| Ensembl | ENSP00000496577.1 | 1 | Standard | |
| Ensembl | ENSP00000496577.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| socs1a | Danio rerio | Structure: neutrophil Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Type II diabetes mellitus - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Toxoplasmosis - Homo sapiens (human)
- Prolactin signaling pathway - Homo sapiens (human)
Biological Process
- regulation of protein phosphorylation
- negative regulation of protein kinase activity
- JAK-STAT cascade
- regulation of activation of Janus kinase activity
- protein ubiquitination
Molecular Function
- protein kinase inhibitor activity
- insulin-like growth factor receptor binding
- protein binding
- kinase inhibitor activity
- protein kinase binding
Cellular Component
- nucleoplasm
- cytoplasm
- cytosol
- phosphatidylinositol 3-kinase complex
- cytoplasmic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000332029
- Coding exons
- 1
- Length
- 1775
- Individuals with no LoFs
- 117046
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 117047
- p
- 0.00000427
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.829 | 67 | 89.0 | 0.753 | 0.00000417 | 1285 |
| Missense (PolyPhen) | 8 | 28.827 | 0.27752 | 404 | ||
| Synonymous | -3.09 | 66 | 40.9 | 1.61 | 0.00000190 | 464 |
| Loss of Function | 1.53 | 0 | 2.73 | 0.00 | 1.19e-7 | 34 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00010 | 0.00010 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS1 is involved in negative regulation of cytokines that signal through the JAK/STAT3 pathway. Through binding to JAKs, inhibits their kinase activity. In vitro, also suppresses Tec protein- tyrosine activity. Appears to be a major regulator of signaling by interleukin 6 (IL6) and leukemia inhibitory factor (LIF). Regulates interferon-gamma mediated sensory neuron survival (By similarity). Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Seems to recognize JAK2. SOCS1 appears to be a negative regulator in IGF1R signaling pathway. {ECO:0000250|UniProtKB:O35716, ECO:0000269|PubMed:11278610, ECO:0000269|PubMed:11313480}.;
Recessive Scores
- pRec
- 0.544
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |