TBX21

Chr 17AR

T-box transcription factor 21

Also known as: IMD88, T-PET, T-bet, TBET, TBLYM

NCBI Gene: 30009ENSG00000073861UniProt: Q9UL17

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Immunodeficiency 88MIM #619630
AR
{Asthma, aspirin-induced, susceptibility to}MIM #208550
AR
Asthma and nasal polypsMIM #208550
AR
UniProtAsthma, with nasal polyps and aspirin intolerance
1
Active trials
89
ClinVar variants
9
Pathogenic / LP
1.4
Missense Z
0.23
LOEUF· LoF intolerant
13
Pubs (2 yr)
Clinical Summary— TBX21
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 69 VUS of 89 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.23LOEUF
pLI 0.996
Z-score 4.04
OE 0.05 (0.02–0.23)
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.
1.40Z-score
OE missense 0.77 (0.69–0.86)
222 obs / 288.7 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.0.05 (0.02–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.69–0.86)
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.0.91
0≤1.21.6
LoF obs/exp: 1 / 21.0Missense obs/exp: 222 / 288.7Syn Z: 0.78

ClinVar Variant Classifications

89 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic1
VUS69
Likely Benign8
Benign3
8
Pathogenic
1
Likely Pathogenic
69
VUS
8
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
7
0
8
Likely Pathogenic
0
0
1
0
1
VUS
0
66
3
0
69
Likely Benign
0
1
3
4
8
Benign
0
1
0
2
3
Total06914689

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

View in ClinVar →

Protein Context — Lollipop Plot

TBX21 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Immunodeficiency 88

MIM #619630

Molecular basis of disorder known

Autosomal recessive

{Asthma, aspirin-induced, susceptibility to}

MIM #208550

Molecular basis of disorder known

Autosomal recessive

Asthma and nasal polyps

MIM #208550

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma.
Zhou J et al.·Mol Cancer
2023
Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.
Heavican TB et al.·Blood
2019
Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis.
Franken A et al.·J Immunother Cancer
2022
Intestinal IL-33 promotes microbiota-derived trimethylamine N -oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α.
Hai S et al.·Hepatology
2025
Early multiple sclerosis activity associated with TBX21+CD21loCXCR3+ B cell expansion resembling EBV-induced phenotypes.
SoRelle ED et al.·JCI Insight
2025
CK2B Induces CD8(+) T-Cell Exhaustion through HDAC8-Mediated Epigenetic Reprogramming to Limit the Efficacy of Anti-PD-1 Therapy in Non-Small-Cell Lung Cancer.
Liu S et al.·Adv Sci (Weinh)
2025
Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach.
Amador C et al.·Mod Pathol
2025
Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice.
Amador C et al.·J Clin Oncol
2022
Classification and diagnostic evaluation of nodal T- and NK-cell lymphomas.
Feldman AL et al.·Virchows Arch
2023Review
Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.
Shi Z et al.·J Neuroinflammation
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
TBX21, the Master regulator of the type 1 immune response, overexpresses in the leukocytes of peripheral blood in patients with late-onset Alzheimer's disease
Fatemi Langroudi SR et al.·Immun Ageing
2023Cohort
Correlation of TBX21 gene polymorphisms with ankylosing spondylitis in a Chinese population.
Li L et al.·Int J Immunogenet
2024
Clinicopathological comparison between PTCL-TBX21 and PTCL-GATA3 in Japanese patients
Shimasaki Y et al.·Cancer Med
2024Cohort
Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy
Miura M et al.·PLoS One
2024Cohort
TBX21 Methylation as a Potential Regulator of Immune Suppression in CMS1 Subtype Colorectal Cancer
Shen Y et al.·Cancers (Basel)
2022
Construction and validation of prognostic signature for transcription factors regulating T cell exhaustion in hepatocellular carcinoma
Jin X et al.·Medicine (Baltimore)
2024
Association of TBX21 gene polymorphisms and acute anterior uveitis risk in a Chinese population: A case-control study.
Shan J et al.·Exp Eye Res
2023
Comprehensive bioinformatics analysis uncover molecular pathways shared between osteoarthritis and atherosclerosis
Jin Y et al.·BMC Musculoskelet Disord
2025
Top 8 full-text resultsSearch PubTator3 ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Stroke, AcuteNeuroprotectionIschemic Conditioning

Effectiveness and Biological Mechanism of Direct Ischemic Post-conditioning for Acute Stroke Patients Due to Large Vessel Occlusion

RECRUITING
NCT06545734Phase PHASE2Tianjin Huanhu HospitalStarted 2023-02-05
Direct Ischemic Post-conditioningEndovascular therapy

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