STAT5B
protein-codingsignal transducer and activator of transcription 5B, the group of SH2 domain containing
Gene summary
The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein mediates the signal transduction triggered by various cell ligands, such as IL2, IL4, CSF1, and different growth hormones. It has been shown to be involved in diverse biological processes, such as TCR signaling, apoptosis, adult mammary gland development, and sexual dimorphism of liver gene expression. This gene was found to fuse to retinoic acid receptor-alpha (RARA) gene in a small subset of acute promyelocytic leukemias (APLL). The dysregulation of the signaling pathways mediated by this protein may be the cause of the APLL. [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 ~89.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100211
Submitter: PanelApp Australia
Inheritance Pattern: SD
Disease ID:MONDO:0100210
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0100219
Submitter: ClinGen
*STAT5B* was first reported in relation to autosomal dominant growth hormone insensitivity syndrome with immune dysregulation 2 in 1998 (Iida K et al. PMID:9467570). GHISID2 is an autosomal dominant form of growth hormone insensitivity syndrome, a congenital disease characterized by short stature, growth hormone deficiency in the presence of normal to elevated circulating concentrations of growth hormone, resistance to exogeneous growth hormone therapy, and recurrent infections. Some patients may have features of mild immune dysregulation, such as eczema, increased serum IgE, asthma, or celiac disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities, GHISID-2 (OMIM:618985), GHISID-1 (OMIM:245590). The split curation for autosomal dominant growth hormone insensitivity syndrome with immune dysregulation 2 has been curated separately. Nine variants (missense, in-frame indel, nonsense) that have been reported in nine probands in five publications (PMIDs: 29844444, 20606392, 27234692, 29188236, 31902742) are included in this curation. Several functional studies of proband variants show non-stable expression and/or limited immunodetection. The mechanism of pathogenicity appears to be dominant negative. This gene-disease relationship is also supported by animal models and expression studies (PMIDs: 37162340, 22912632, 37162340, 9575217). Zebrafish models highlight growth defects (including cyclopia and pericardial edema), deficiency of IFG-I transcription in the liver, and defective postnatal skeletal muscle development (including bent spine). Biochemical function studies indicate that *STAT5B* is essential for IL-2–driven transcription of *IL2RA* (*CD25*) and *FOXP3*, crucial for Treg lineage specification. *STAT5B* deficiency leads to decreased Treg numbers and impaired function, promoting autoimmunity (e.g., eczema, autoimmune thyroiditis). In summary, there is moderate evidence supporting the relationship between *STAT5B* and autosomal dominant growth hormone insensitivity syndrome with immune dysregulation 2. 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 PIRD GCEP on the meeting date January 20, 2026 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0100211
Submitter: ClinGen
*STAT5B* was first reported in relation to autosomal recessive growth hormone insensitivity syndrome with immune dysregulation 1 in 1998 (Iida K et al. PMID:9467570). GHISID1 is an autosomal recessive form of growth hormone insensitivity syndrome, a congenital disease characterized by short stature, growth hormone deficiency in the presence of normal to elevated circulating concentrations of growth hormone, resistance to exogeneous growth hormone therapy, and recurrent infections. Patients often have features of immune dysregulation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities, GHISID-2 (OMIM:618985), GHISID-1 (OMIM:245590). The split curation for autosomal dominant growth hormone insensitivity syndrome with immune dysregulation 2 has been curated separately. Six variants (missense, in-frame indel, nonsense) that have been reported in six probands in six publications (PMIDs: 13679528, 15827093, 17389811, 16787985, 17030597, 39037394) are included in this curation. Several functional studies of proband variants show non-stable expression and/or limited immunodetection. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models and expression studies (PMIDs: 17158201, 22912632, 37162340). Zebrafish and mouse models highlight growth defects (including cyclopia and pericardial edema), deficiency of IFG-I transcription in the liver, and defective postnatal skeletal muscle development (including bent spine). Biochemical function studies indicate that *STAT5B* is essential for IL-2–driven transcription of *IL2RA* (*CD25*) and *FOXP3*, crucial for Treg lineage specification. *STAT5B* deficiency leads to decreased Treg numbers and impaired function, promoting autoimmunity (e.g., eczema, autoimmune thyroiditis). In summary, there is definitive evidence supporting the relationship between *STAT5B* and autosomal recessive growth hormone insensitivity syndrome with immune dysregulation 1. 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 PIRD GCEP on the meeting date December 16, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0100211
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100211
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100219
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100219
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0100211
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015892
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0100211
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal
Intervention: Allergy/Immunology/Infectious; Endocrine
Rationale: In Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant, medical management (eg, with growth or hormone or recombinant human IGF-1) might be effective, though this remains to be fully evaluated; Individuals with Growth hormone insensitivity with immune dysregulation 1, autosomal recessive demonstrate infection susceptibility, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; As relates to growth deficiency in Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, medical management (eg, with with recombinant human IGF-1) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STAT5B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012448.4. 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 | 10 | 177 | 187 | |||
| missense | 3 | 3 | 267 | 6 | 1 | 280 |
| nonsense | 12 | 1 | 2 | 15 | ||
| start loss | 0 | |||||
| frameshift | 11 | 1 | 12 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 5 | 9 | ||
| Total | 27 | 8 | 284 | 183 | 1 | 503 |
Highest pathogenic variant AF is 0.000007440956
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036580.2 | 18 | MANE Select | |
| Ensembl | ENSP00000293328.3 | 18 | MANE Select | |
| Ensembl | ENSP00000398379.2 | 18 | Standard | |
| Ensembl | ENSP00000398379.2 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| stat5a | Danio rerio | Structure: nucleate erythrocyte Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Non-small cell lung cancer - Homo sapiens (human)
- Chronic myeloid leukemia - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Acute myeloid leukemia - Homo sapiens (human)
Biological Process
- luteinization
- natural killer cell differentiation
- regulation of transcription by RNA polymerase II
- JAK-STAT cascade
- female pregnancy
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000293328
- Coding exons
- 18
- Length
- 77540
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.00 | 212 | 451 | 0.470 | 0.0000282 | 5188 |
| Missense (PolyPhen) | 52 | 127.19 | 0.40883 | 1473 | ||
| Synonymous | 0.984 | 172 | 189 | 0.909 | 0.0000126 | 1497 |
| Loss of Function | 5.73 | 5 | 47.8 | 0.105 | 0.00000251 | 495 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Binds to the GAS element and activates PRL-induced transcription. Positively regulates hematopoietic/erythroid differentiation. {ECO:0000269|PubMed:20702587, ECO:0000269|PubMed:8732682}.;
- Disease
- DISEASE: Growth hormone insensitivity with immunodeficiency (GHII) [MIM:245590]: A disease characterized by short stature, growth hormone deficiency in the presence of normal to elevated circulating concentrations of growth hormone, resistance to hexogeneous growth hormone therapy, and recurrent infections. {ECO:0000269|PubMed:13679528, ECO:0000269|PubMed:15827093, ECO:0000269|PubMed:22419735}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0917
- RVIS EVS
- -0.89
- RVIS percentile EVS
- 10.3
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |