FOXP3

Chr XXLR

forkhead box P3

Also known as: AIID, DIETER, IPEX, JM2, PIDX, XPID

NCBI Gene: 50943ENSG00000049768UniProt: Q9BZS1

The protein encoded by this gene is a member of the forkhead/winged-helix family of transcriptional regulators. Defects in this gene are the cause of immunodeficiency polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Immunodysregulation, polyendocrinopathy, and enteropathy, X-linkedMIM #304790
XLR
UniProtImmunodeficiency polyendocrinopathy, enteropathy, X-linked syndrome
12
Active trials
64
Pathogenic / LP
309
ClinVar variants
7
Pubs (1 yr)
1.7
Missense Z
0.20
LOEUF· LoF intolerant
Clinical Summary— FOXP3
🧬
Gene-Disease Validity (ClinGen)
immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
64 Pathogenic / Likely Pathogenic· 117 VUS of 309 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
📖
GeneReview available — FOXP3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.20LOEUF
pLI 0.994
Z-score 3.63
OE 0.00 (0.00–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.67Z-score
OE missense 0.64 (0.55–0.75)
109 obs / 170.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.55–0.75)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.82
0≤1.21.6
LoF obs/exp: 0 / 15.3Missense obs/exp: 109 / 170.4Syn Z: 1.19
DN
0.3892th %ile
GOF
0.3391th %ile
LOF
0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 20% of P/LP variants are LoF · LOEUF 0.20

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

309 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic9
VUS117
Likely Benign96
Benign20
Conflicting12
55
Pathogenic
9
Likely Pathogenic
117
VUS
96
Likely Benign
20
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
7
41
0
55
Likely Pathogenic
6
2
0
1
9
VUS
0
97
17
3
117
Likely Benign
0
6
49
41
96
Benign
0
2
17
1
20
Conflicting
—12
Total1311412446309

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FOXP3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FOXP3-related IPEX syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Chronic Myelomonocytic Leukemia

Chimeric Antigen Receptor T Cell Therapy Redirected to CD4 (CD4CAR)as a Second Line Treatment for Chronic Myelomonocytic Leukemia, CMML.

RECRUITING
NCT06071624Phase PHASE1Huda SalmanStarted 2024-02-21
CD4CAR
Prostate Cancer

Hypofractionated, Dose Escalation Radiotherapy for High Risk Adenocarcinoma of the Prostate

ACTIVE NOT RECRUITING
NCT01444820Phase PHASE3Sir Mortimer B. Davis - Jewish General HospitalStarted 2012-01
hypofractionationconventional
Cervical High Grade Squamous Intraepithelial LesionCervical Intraepithelial Neoplasia Grade 2/3CIN 2/3

Predicting Response In Cervical Intraepithelial Neoplasia to Topical Imiquimod Treatment

RECRUITING
NCT05405270Catharina Ziekenhuis EindhovenStarted 2022-06-01
Imiquimod3x vaginal swab for microbiome analysisExpectative management
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation
Glioblastoma

DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab

ACTIVE NOT RECRUITING
NCT03688178Phase PHASE2Annick Desjardins, MDStarted 2020-08-26
Human CMV pp65-LAMP mRNA-pulsed autologous DCsTemozolomideVarlilumab
Immune System ToleranceDepressionObesity

ESAN II - Energy Sensing in Depression

RECRUITING
NCT05432362Phase NAMedical University of GrazStarted 2019-02-25
Aronia JuicePlacebo
Type 1 Diabetes

Characterization of Autoreactive Regulatory and Conventional CD4 T Cells in Recent Onset Type 1 Diabetes and Control Individuals

RECRUITING
NCT06427421Phase NAAssistance Publique - Hôpitaux de ParisStarted 2025-05-06
Frequency of Treg and TeffsPhenotype of Treg and TeffsRNA seq analysis
Type1 Diabetes Mellitus

EXtremely Early-onset Type 1 Diabetes EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study)

RECRUITING
NCT03369821University of ExeterStarted 2017-09-19
Beta Cell Loss and Immune FunctionImmune Function with RNAseq
Type 1 Diabetes Mellitus

Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2)

ACTIVE NOT RECRUITING
NCT03941132Phase PHASE2, PHASE3University of British ColumbiaStarted 2021-01-04
UstekinumabPlacebo
Malnutrition PregnancyMalnutrition in ChildrenMalnutrition (Calorie)

Early Life Malnutrition, Environmental Enteric Dysfunction and Microbiome Trajectories

RECRUITING
NCT07195006University of ZimbabweStarted 2025-01-27
Malnutrition in pregnancy as exposurePoor WASH living conditions as exposure
Diabetes MellitusPancreas TransplantationAllograft Rejection

The Norwegian Pancreas Transplantation (PTx) Study

ENROLLING BY INVITATION
NCT01957696Oslo University HospitalStarted 2013-09
Meningiomas

An Open-Label Phase II Study of Nivolumab or Nivolumab/Ipilimumab in Adult Participants With Progessive/ Recurrent Meningioma

ACTIVE NOT RECRUITING
NCT02648997Phase PHASE2Dana-Farber Cancer InstituteStarted 2016-03
Nivolumab - 240 mgIpilimumab - 1 mg/kgNivolumab - 480 mg
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
STAU1-mediated stabilization of ITGB5 enhances FOXP3 transcriptional activity to form a self-reinforcing metastasis circuit in colorectal cancer.
Wang Y et al.·Cancer Lett
2026
Regulatory-like FOXP3+Helios+ CD4+ T conventional cells correlate with T cell activation after Orca-T immunotherapy.
Bader CS et al.·Blood
2026
Cytokines Associated with Activation of CD4+CD25+Foxp3+ T Regulatory Cells.
Al-Atiyah R et al.·Int J Mol Sci
2026
Malathion-induced neurological alterations associated with dysregulation of RORγt/STAT3/IL-17 and FOXP3/STAT5/IL-10 pathways: potential neuroprotective effects of BCG.
Aborehab NM et al.·Naunyn Schmiedebergs Arch Pharmacol
2026
The likely possibility of predicting treatment outcomes of cervical lesions using serum FOXP3 and P16INK4A as shown by a cohort study in South Western Uganda.
Ssedyabane F et al.·Discov Oncol
2026Cohort
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients