TBX1

Chr 22AD

T-box transcription factor 1

Also known as: CAFS, CATCH22, CTHM, DGCR, DGS, DORV, TBX1C, TGA

NCBI Gene: 6899ENSG00000184058UniProt: O43435

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 product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Conotruncal anomaly face syndromeMIM #217095
DiGeorge syndromeMIM #188400
AD
Tetralogy of FallotMIM #187500
AD
Velocardiofacial syndromeMIM #192430
AD
UniProtConotruncal heart malformations
596
ClinVar variants
68
Pathogenic / LP
0.84
pLI score
0
Active trials
Clinical Summary— TBX1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.84) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
68 Pathogenic / Likely Pathogenic· 284 VUS of 596 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.43LOEUF
pLI 0.837
Z-score 3.07
OE 0.14 (0.05–0.43)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.74Z-score
OE missense 0.86 (0.76–0.97)
189 obs / 219.7 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.0.14 (0.05–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.76–0.97)
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.1.46
0≤1.21.6
LoF obs/exp: 2 / 14.7Missense obs/exp: 189 / 219.7Syn Z: -3.55

ClinVar Variant Classifications

596 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic15
VUS284
Likely Benign218
Benign21
Conflicting5
53
Pathogenic
15
Likely Pathogenic
284
VUS
218
Likely Benign
21
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
41
0
53
Likely Pathogenic
9
1
5
0
15
VUS
5
237
37
5
284
Likely Benign
0
6
68
144
218
Benign
0
0
21
0
21
Conflicting
—5
Total26244172149596

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

View in ClinVar →

Protein Context — Lollipop Plot

TBX1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TBX1-related 22q11.2 deletion syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Conotruncal anomaly face syndrome

MIM #217095

Molecular basis of disorder known

DiGeorge syndrome

MIM #188400

Molecular basis of disorder known

Autosomal dominant

Tetralogy of Fallot

MIM #187500

Molecular basis of disorder known

Autosomal dominant

Velocardiofacial syndrome

MIM #192430

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TBX1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
22q11.2 duplications: Expanding the clinical presentation.
Bartik LE et al.·Am J Med Genet A
2022
Central 22q11.2 deletions.
Rump P et al.·Am J Med Genet A
2014
Review of the Pathophysiology and Clinical Manifestations of 22q11.2 Deletion and Duplication Syndromes.
Purow J et al.·Clin Rev Allergy Immunol
2025Review
Velo-cardio-facial syndrome.
Shprintzen RJ et al.·Curr Opin Pediatr
2005Review
Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome.
Eom TY et al.·Nat Commun
2024
Dissecting contiguous gene defects: TBX1.
Baldini A·Curr Opin Genet Dev
2005Review
Intratumor heterogeneity in human parathyroid tumors.
Verdelli C et al.·Histol Histopathol
2020Review
Clinical and molecular effects of CHD7 in the heart.
Corsten-Janssen N et al.·Am J Med Genet C Semin Med Genet
2017Review
Diagnosis of prenatal 22q11.2 duplication syndrome: a two-case study.
Li H et al.·J Genet
2023Case report
Genetic Origins of Tetralogy of Fallot.
Morgenthau A et al.·Cardiol Rev
2018Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools