TBX1

Chr 22AD

T-box transcription factor 1

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

NCBI Gene: 6899ENSG00000184058UniProt: O43435OMIM: 602054

TBX1 encodes a transcription factor that regulates developmental processes, particularly those involving neural crest cell development. Haploinsufficiency causes DiGeorge syndrome/velocardiofacial syndrome and related 22q11.2 deletion phenotypes including conotruncal heart defects and tetralogy of Fallot through autosomal dominant inheritance. Loss-of-function mutations disrupt normal transcriptional regulation of genes critical for pharyngeal arch and cardiac outflow tract development.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.434 OMIM phenotypes
Clinical Summary— TBX1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.84) — some intolerance to loss-of-function variants.
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ClinVar Variants
60 unique Pathogenic / Likely Pathogenic· 268 VUS of 499 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — TBX1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
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
0.74Z-score
OE missense 0.86 (0.76–0.97)
189 obs / 219.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.14 (0.05–0.43)
0≤0.351.4
Missense OE0.86 (0.76–0.97)
0≤0.61.4
Synonymous OE1.46
0≤1.21.6
LoF obs/exp: 2 / 14.7Missense obs/exp: 189 / 219.7Syn Z: -3.55
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTBX1-related 22q11.2 deletion syndromeLOFAD
DN
0.3892th %ile
GOF
0.3590th %ile
LOF
0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 35% of P/LP variants are LoF · LOEUF 0.43
GOF1 literature citation

Literature Evidence

GOFWe report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-oPMID:17273972
LOFTbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in micePMID:11242049

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

499 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic13
VUS268
Likely Benign162
Benign1
Conflicting3
47
Pathogenic
13
Likely Pathogenic
268
VUS
162
Likely Benign
1
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
0
36
0
47
Likely Pathogenic
10
1
2
0
13
VUS
10
240
15
3
268
Likely Benign
0
8
36
118
162
Benign
0
0
1
0
1
Conflicting
—3
Total3124990121494

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
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
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