FOXP3

forkhead box P3, the group of Forkhead boxes

Basic information

Region (hg38): X:49250438-49264800

Previous symbols: [ "IPEX" ]

Links

ENSG00000049768 ∙ NCBI:50943 ∙ OMIM:300292 ∙ HGNC:6106 ∙ Uniprot:Q9BZS1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Definitive), mode of inheritance: XLR
• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Strong), mode of inheritance: XL
• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Supportive), mode of inheritance: XL
• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Definitive), mode of inheritance: XL
• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX)	XL	Allergy/Immunology/Infectious	For neutropenia, G-CSF can be effective; Bone marrow transplantation has been reported as effective if performed early; Prophylactic antibiotics can be beneficial; Immunosuppressive agents may be helpful	Allergy/Immunology/Infectious; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Renal	7040622; 2246696; 8482279; 8777684; 11120765; 11396442; 11137993; 11295725; 11137992; 20301297; 20842625; 21979562; 21741320; 21865090; 22132891; 23534934
The condition may involve infectious and autoimmune manifestations

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FOXP3 gene.

• Insulin-dependent diabetes mellitus secretory diarrhea syndrome (17 variants)
• not provided (4 variants)
• Hydrops fetalis (1 variants)
• FOXP3-related disorder (1 variants)
• Bone marrow hypocellularity;Pancytopenia;Anemia (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FOXP3 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			1	45	4	50
missense	8	11	104	17	8	148
nonsense	2	1				3
start loss	1					1
frameshift	2	2				4
inframe indel	1	1	1			3
splice donor/acceptor (+/-2bp)	5	6				11
splice region		1	12	9	2	24
non coding			3	31	19	53
Total	19	21	109	93	31

Highest pathogenic variant AF is 0.0000178

Variants in FOXP3

This is a list of pathogenic ClinVar variants found in the FOXP3 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-49250456-T-C		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Dec 19, 2019)
X-49250467-C-G		not specified	Uncertain significance (Jul 17, 2020)
X-49250661-C-T		not specified	Likely benign (-)
X-49251322-TTGATCTTGAGGTCAGGGG-CA		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Pathogenic (Jan 01, 2001)
X-49251335-C-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Likely benign (Dec 14, 2023)
X-49251335-CAG-C		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Pathogenic (Jan 01, 2001)
X-49251336-AGGGGC-A		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Aug 12, 2021)
X-49251345-G-A		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Likely benign (Oct 13, 2023)
X-49251350-G-C		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Apr 17, 2020)
X-49251352-G-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Benign/Likely benign (Oct 13, 2023)
X-49251353-T-C		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Likely benign (May 28, 2022)
X-49251358-ACA-G		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Likely pathogenic (Apr 25, 2018)
X-49251359-C-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Pathogenic (-)
X-49251373-C-G		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Jan 28, 2021)
X-49251373-C-T			Likely benign (Nov 01, 2022)
X-49251377-C-G		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Sep 14, 2023)
X-49251377-C-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (May 03, 2021)
X-49251378-T-C		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Oct 27, 2022)
X-49251380-C-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Nov 03, 2023)
X-49251381-G-A		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Nov 12, 2023)
X-49251382-T-A		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Likely benign (Feb 27, 2019)
X-49251383-T-A		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Uncertain significance (Apr 23, 2018)
X-49251389-C-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Benign/Likely benign (Dec 22, 2023)
X-49251390-G-A		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Likely benign (Jun 04, 2023)
X-49251395-TC-T		Insulin-dependent diabetes mellitus secretory diarrhea syndrome	Pathogenic (May 04, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FOXP3	protein_coding	protein_coding	ENST00000376207	11	14392

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.994	0.00576	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.67	109	170	0.640	0.0000136	2763
Missense in Polyphen		22	58.824	0.374		918
Synonymous	1.19	59	71.8	0.821	0.00000586	903
Loss of Function	3.63	0	15.3	0.00	0.00000115	232

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg). Plays an essential role in maintaining homeostasis of the immune system by allowing the acquisition of full suppressive function and stability of the Treg lineage, and by directly modulating the expansion and function of conventional T-cells. Can act either as a transcriptional repressor or a transcriptional activator depending on its interactions with other transcription factors, histone acetylases and deacetylases. The suppressive activity of Treg involves the coordinate activation of many genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of genes encoding cytokines such as interleukin-2 (IL2) and interferon- gamma (IFNG). Inhibits cytokine production and T-cell effector function by repressing the activity of two key transcription factors, RELA and NFATC2 (PubMed:15790681). Mediates transcriptional repression of IL2 via its association with histone acetylase KAT5 and histone deacetylase HDAC7 (PubMed:17360565). Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG via its association with transcription factor RUNX1 (PubMed:17377532). Inhibits the differentiation of IL17 producing helper T-cells (Th17) by antagonizing RORC function, leading to down-regulation of IL17 expression, favoring Treg development (PubMed:18368049). Inhibits the transcriptional activator activity of RORA (PubMed:18354202). Can repress the expression of IL2 and IFNG via its association with transcription factor IKZF4 (By similarity). {ECO:0000250|UniProtKB:Q99JB6, ECO:0000269|PubMed:15790681, ECO:0000269|PubMed:17360565, ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18368049, ECO:0000269|PubMed:21458306, ECO:0000269|PubMed:23169781}.
• Disease: DISEASE: Immunodeficiency polyendocrinopathy, enteropathy, X- linked syndrome (IPEX) [MIM:304790]: Characterized by neonatal onset insulin-dependent diabetes mellitus, infections, secretory diarrhea, thrombocytopenia, anemia and eczema. It is usually lethal in infancy. {ECO:0000269|PubMed:11120765, ECO:0000269|PubMed:11137992, ECO:0000269|PubMed:11137993, ECO:0000269|PubMed:11768393, ECO:0000269|PubMed:18951619, ECO:0000269|PubMed:21458306}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Inflammatory bowel disease (IBD) - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Allograft Rejection;TGF-beta Signaling Pathway;RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs);Transcriptional regulation by RUNX1;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs);RUNX1 regulates transcription of genes involved in WNT signaling;Transcriptional regulation by RUNX1;IL2 signaling events mediated by STAT5;Calcineurin-regulated NFAT-dependent transcription in lymphocytes (Consensus)

Recessive Scores

• pRec: 0.530

Intolerance Scores

• loftool: 0.0262
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.75

Haploinsufficiency Scores

• pHI: 0.387
• hipred: Y
• hipred_score: 0.560
• ghis: 0.460

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.804

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Foxp3
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial 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; endocrine/exocrine gland phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; renal/urinary system phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; digestive/alimentary phenotype; vision/eye phenotype; reproductive system phenotype; 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

Zebrafish Information Network

• Gene name: foxp3a
• Affected structure: intestine
• Phenotype tag: abnormal
• Phenotype quality: swollen

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;B cell homeostasis;cytokine production;myeloid cell homeostasis;CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment;T cell mediated immunity;tolerance induction to self antigen;regulation of T cell anergy;positive regulation of T cell anergy;negative regulation of chronic inflammatory response;negative regulation of T cell cytokine production;positive regulation of peripheral T cell tolerance induction;chromatin remodeling;regulation of transcription, DNA-templated;negative regulation of cell population proliferation;response to virus;regulation of Wnt signaling pathway;negative regulation of histone deacetylation;negative regulation of NF-kappaB transcription factor activity;negative regulation of interferon-gamma production;negative regulation of interleukin-10 production;negative regulation of interleukin-17 production;negative regulation of interleukin-2 production;negative regulation of interleukin-4 production;negative regulation of interleukin-5 production;negative regulation of interleukin-6 production;negative regulation of tumor necrosis factor production;positive regulation of interleukin-4 production;negative regulation of CREB transcription factor activity;positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation;positive regulation of transforming growth factor beta1 production;positive regulation of immature T cell proliferation in thymus;positive regulation of histone acetylation;negative regulation of histone acetylation;negative regulation of cytokine biosynthetic process;T cell activation;negative regulation of T cell proliferation;T cell homeostasis;negative regulation of DNA-binding transcription factor activity;negative regulation of interferon-gamma biosynthetic process;negative regulation of interleukin-2 biosynthetic process;regulation of regulatory T cell differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;negative regulation of activated T cell proliferation;negative regulation of isotype switching to IgE isotypes;regulation of isotype switching to IgG isotypes;negative regulation of cytokine secretion;negative regulation of immune response;T cell receptor signaling pathway;negative regulation of T-helper 17 cell differentiation
• Cellular component: nucleus;nucleoplasm;cytoplasm;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;transcription corepressor activity;protein binding;histone acetyltransferase binding;protein homodimerization activity;histone deacetylase binding;sequence-specific DNA binding;metal ion binding;NF-kappaB binding;NFAT protein binding