STAT1

signal transducer and activator of transcription 1, the group of SH2 domain containing

Basic information

Region (hg38): 2:190908460-191020960

Links

ENSG00000115415 ∙ NCBI:6772 ∙ OMIM:600555 ∙ HGNC:11362 ∙ Uniprot:P42224 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (Moderate), mode of inheritance: AD
• immunodeficiency 31B (Definitive), mode of inheritance: AR
• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (Strong), mode of inheritance: AD
• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (Definitive), mode of inheritance: AD
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (Supportive), mode of inheritance: AD
• immunodeficiency 31B (Supportive), mode of inheritance: AR
• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (Supportive), mode of inheritance: AD
• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (Strong), mode of inheritance: AD
• immunodeficiency 31B (Strong), mode of inheritance: AR
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 31A; Immunodeficiency 31B; Immunodeficiency 31C	AD/AR	Allergy/Immunology/Infectious; Oncologic	Individuals with autosomal recessive forms demonstrate susceptibility to severe viral and mycobacterial infections (including lethal infections), and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals with heterozygous forms may besusceptible to candiasis, and may be susceptible to neoplasms including carcinoma, as well as autoimmune thyroid disease, and awareness may allow prompt diagnosis and treatment; HSCT has beeen described in some STAT1-related conditions	Allergy/Immunology/Infectious; Oncologic	4213132; 15502825; 22990144; 23436467; 24026681; 27232954; 30691927

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the STAT1 gene.

• not provided (10 variants)
• Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (7 variants)
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency;Immunodeficiency 31B;Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (5 variants)
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency;Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;Immunodeficiency 31B (5 variants)
• Immunodeficiency 31B;Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency;Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (4 variants)
• Immunodeficiency 31B;Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (4 variants)
• Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency;Immunodeficiency 31B (3 variants)
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (2 variants)
• Immunodeficiency 31B (2 variants)
• See cases (2 variants)
• Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;Immunodeficiency 31B;Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (2 variants)
• STAT1-related disorder (2 variants)
• Chronic mucocutaneous candidiasis (1 variants)
• 7 conditions (1 variants)
• Developmental and epileptic encephalopathy, 71 (1 variants)
• Inherited Immunodeficiency Diseases (1 variants)
• Immunodeficiency 31B;Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (1 variants)
• 6 conditions (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the STAT1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	113	5	126
missense	20	27	144	1		192
nonsense	3	2				5
start loss						0
frameshift	6	2	1			9
inframe indel			6			6
splice donor/acceptor (+/-2bp)	1	3				4
splice region			24	34	3	61
non coding	1	3	47	105	43	199
Total	31	37	206	219	48

Highest pathogenic variant AF is 0.00000657

Variants in STAT1

This is a list of pathogenic ClinVar variants found in the STAT1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-190910319-A-C		Inborn genetic diseases	Uncertain significance (Sep 30, 2021)
2-190910320-A-G			Uncertain significance (-)
2-190921012-A-AT		GLS-related disorder	Likely benign (Jul 16, 2019)
2-190921032-AAAT-A			Uncertain significance (Jun 12, 2020)
2-190921143-A-C			Likely pathogenic (Jul 26, 2022)
2-190923946-G-A			Uncertain significance (Mar 29, 2023)
2-190923960-G-A			Uncertain significance (May 01, 2019)
2-190927327-T-C		Developmental and epileptic encephalopathy, 71	Likely pathogenic (Apr 14, 2023)
2-190927351-G-T		GLS-related disorder	Benign (Dec 01, 2023)
2-190927370-G-A			Uncertain significance (Dec 20, 2022)
2-190927384-A-G		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
2-190927469-A-G			Likely pathogenic (Dec 01, 2023)
2-190927475-C-T		Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development	Uncertain significance (Mar 25, 2024)
2-190930456-C-G		Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development	Pathogenic (May 01, 2019)
2-190930466-T-TG		Developmental and epileptic encephalopathy, 71	Pathogenic (Mar 22, 2022)
2-190930534-T-A		Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development	Uncertain significance (Sep 08, 2021)
2-190931645-A-C		GLS-related disorder	Benign (Sep 10, 2019)
2-190932730-A-G		GLS-related disorder	Likely benign (May 28, 2019)
2-190932753-A-C		GLS-related disorder	Uncertain significance (Sep 29, 2023)
2-190953548-CTTTCT-C		GLS-related disorder	Likely benign (Feb 26, 2020)
2-190953576-G-A		GLS-related disorder	Likely benign (Jan 01, 2023)
2-190953597-A-C		GLS-related disorder	Benign (Dec 31, 2019)
2-190962889-T-C		Inborn genetic diseases	Uncertain significance (May 23, 2024)
2-190962916-C-T		Tracheoesophageal fistula	Likely pathogenic (Jul 01, 2019)
2-190962937-A-G		GLS-related disorder	Benign (May 28, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
STAT1	protein_coding	protein_coding	ENST00000361099	23	56603

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000148	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.15	114	406	0.281	0.0000229	5031
Missense in Polyphen		19	136.74	0.13895		1752
Synonymous	-0.228	156	152	1.02	0.00000926	1319
Loss of Function	5.95	4	48.9	0.0818	0.00000230	568

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.000131	0.000131
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426). ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788). It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. {ECO:0000269|PubMed:12764129, ECO:0000269|PubMed:12855578, ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426, ECO:0000269|PubMed:9724754}.
• Disease: DISEASE: Immunodeficiency 31B (IMD31B) [MIM:613796]: A disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness. {ECO:0000269|PubMed:12590259, ECO:0000269|PubMed:20841510, ECO:0000269|PubMed:23709754}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 31A (IMD31A) [MIM:614892]: A form of Mendelian susceptibility to mycobacterial disease, a rare condition caused by impairment of interferon-gamma mediated immunity. It is characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. Clinical outcome severity depends on the degree of impairment of interferon-gamma mediated immunity. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. IMD31A has low penetrance, and affected individuals have relatively mild disease and good prognosis. IMD31A confers a predisposition to mycobacterial infections only, with no increased susceptibility to viral infections. {ECO:0000269|PubMed:11452125, ECO:0000269|PubMed:16934001, ECO:0000269|PubMed:22573496}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 31C (IMD31C) [MIM:614162]: A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. {ECO:0000269|PubMed:21714643, ECO:0000269|PubMed:21727188, ECO:0000269|PubMed:23709754, ECO:0000269|PubMed:25288569, ECO:0000269|PubMed:26514428}. Note=The disease is caused by mutations affecting the gene represented in this entry. STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643). {ECO:0000269|PubMed:21714643}.
• Pathway: Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Jak-STAT signaling pathway - Homo sapiens (human);Influenza A - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Necroptosis - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);JAK-STAT-Core;IL-5 Signaling Pathway;Regulation of toll-like receptor signaling pathway;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Leptin signaling pathway;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Prolactin Signaling Pathway;IL-7 Signaling Pathway;Type III interferon signaling;IL-9 Signaling Pathway;Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway;AGE-RAGE pathway;Allograft Rejection;Interleukin-11 Signaling Pathway;Adipogenesis;Oncostatin M Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;JAK-STAT;Endoderm Differentiation;Kit receptor signaling pathway;IL-6 signaling pathway;IL-4 Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;Chemokine signaling pathway;PDGFR-beta pathway;p38 MAPK Signaling Pathway;Interleukin-4 and 13 signaling;Ebola Virus Pathway on Host;The human immune response to tuberculosis;Ebola Virus Pathway on Host;EGF-EGFR Signaling Pathway;Endochondral Ossification;IL-2 Signaling Pathway;TGF-beta Receptor Signaling;EPO Receptor Signaling;Interferon type I signaling pathways;Type II interferon signaling (IFNG);Toll-like Receptor Signaling Pathway;Interleukin-4 and 13 signaling;Transcriptional regulation by RUNX2;Interleukin-12 family signaling;Disease;Signal Transduction;Gene expression (Transcription);Signaling by Interleukins;inhibition of cellular proliferation by gleevec;bioactive peptide induced signaling pathway;egf signaling pathway;p38 mapk signaling pathway;ifn gamma signaling pathway;Growth hormone receptor signaling;il22 soluble receptor signaling pathway;ifn alpha signaling pathway;mapkinase signaling pathway;Generic Transcription Pathway;Prolactin;Cytokine Signaling in Immune system;JAK STAT MolecularVariation 1;Signaling by PDGF;RNA Polymerase II Transcription;Regulation of IFNG signaling;TCR;Oncostatin_M;Immune System;IFN alpha signaling;IFN gamma signaling;KitReceptor;BCR;NOTCH3 Intracellular Domain Regulates Transcription;Signaling by NOTCH3;Signaling by NOTCH;pdgf signaling pathway;IL-5 signaling;tpo signaling pathway;EGFR1;SHP2 signaling;Glucocorticoid receptor regulatory network;CXCR4-mediated signaling events;ErbB1 downstream signaling;JAK STAT MolecularVariation 2;Signaling events mediated by TCPTP;JAK STAT pathway and regulation;IL2;IL11;EPO signaling;IL2-mediated signaling events;Downstream signal transduction;Interferon gamma signaling;IFN-gamma pathway;IL4;EPO signaling pathway;Signaling by SCF-KIT;Signaling by FGFR in disease;IL5;Leptin;Interleukin-27 signaling;IL6;TNFalpha;IL-7;Signaling by cytosolic FGFR1 fusion mutants;FGFR1 mutant receptor activation;Signaling by FGFR1 in disease;Regulation of IFNA signaling;Interferon alpha/beta signaling;Signaling by Receptor Tyrosine Kinases;IL23-mediated signaling events;GMCSF-mediated signaling events;IL27-mediated signaling events;TNF receptor signaling pathway ;Diseases of signal transduction;ISG15 antiviral mechanism;Antiviral mechanism by IFN-stimulated genes;Interferon Signaling;Signaling events mediated by Stem cell factor receptor (c-Kit);PDGFR-beta signaling pathway;Interleukin-6 signaling;Interleukin-6 family signaling;IL6-mediated signaling events;FGF signaling pathway;IL12-mediated signaling events;TSLP;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.962

Intolerance Scores

• loftool: 0.151
• rvis_EVS: -0.29
• rvis_percentile_EVS: 33.2

Haploinsufficiency Scores

• pHI: 0.874
• hipred: Y
• hipred_score: 0.825
• ghis: 0.568

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Stat1
• Phenotype: neoplasm; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); muscle phenotype; digestive/alimentary phenotype; endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: stat1b
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;negative regulation of endothelial cell proliferation;positive regulation of mesenchymal cell proliferation;positive regulation of defense response to virus by host;negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis;transcription by RNA polymerase II;positive regulation of transcription of Notch receptor target;JAK-STAT cascade;response to nutrient;blood circulation;response to mechanical stimulus;macrophage derived foam cell differentiation;viral process;negative regulation of angiogenesis;cytokine-mediated signaling pathway;positive regulation of interferon-alpha production;cellular response to insulin stimulus;tumor necrosis factor-mediated signaling pathway;response to cytokine;response to interferon-beta;cellular response to interferon-beta;interleukin-9-mediated signaling pathway;interleukin-21-mediated signaling pathway;response to hydrogen peroxide;regulation of apoptotic process;negative regulation of I-kappaB kinase/NF-kappaB signaling;response to peptide hormone;endothelial cell migration;positive regulation of erythrocyte differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;negative regulation by virus of viral protein levels in host cell;positive regulation of smooth muscle cell proliferation;response to cAMP;defense response to virus;positive regulation of nitric-oxide synthase biosynthetic process;interferon-gamma-mediated signaling pathway;regulation of interferon-gamma-mediated signaling pathway;type I interferon signaling pathway;renal tubule development;interleukin-6-mediated signaling pathway;interleukin-27-mediated signaling pathway;interleukin-35-mediated signaling pathway;cellular response to interferon-gamma;cellular response to organic cyclic compound;metanephric mesenchymal cell proliferation involved in metanephros development;metanephric mesenchymal cell differentiation;negative regulation of metanephric nephron tubule epithelial cell differentiation
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;nucleolus;cytoplasm;cytosol;axon;dendrite;protein-containing complex;perinuclear region of cytoplasm
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II core promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;double-stranded DNA binding;DNA-binding transcription factor activity;tumor necrosis factor receptor binding;protein binding;RNA polymerase II general transcription initiation factor activity;enzyme binding;CCR5 chemokine receptor binding;histone acetyltransferase binding;nuclear hormone receptor binding;histone binding;identical protein binding;protein homodimerization activity;ubiquitin-like protein ligase binding;cadherin binding;protein phosphatase 2A binding;repressing transcription factor binding;promoter-specific chromatin binding