TBX6

Chr 16ADAR

T-box transcription factor 6

NCBI Gene: 6911ENSG00000149922UniProt: O95947

T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal. Acts in part by down-regulating, a specific enhancer (N1) of SOX2, to inhibit neural development. Seems to play also an essential role in left/right axis determination and acts through effects on Notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia (By similarity)

Primary Disease Associations & Inheritance

Spondylocostal dysostosis 5MIM #122600
ADAR
633
ClinVar variants
133
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— TBX6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
133 Pathogenic / Likely Pathogenic· 180 VUS of 633 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.69LOEUF
pLI 0.007
Z-score 2.57
OE 0.37 (0.21–0.69)
Tolerant

Typical tolerance to LoF variation

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.
0.54Z-score
OE missense 0.91 (0.82–1.01)
254 obs / 279.2 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.0.37 (0.21–0.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.82–1.01)
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.0.98
0≤1.21.6
LoF obs/exp: 7 / 19.1Missense obs/exp: 254 / 279.2Syn Z: 0.17

ClinVar Variant Classifications

633 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic120
Likely Pathogenic13
VUS180
Likely Benign93
Benign9
Conflicting3
120
Pathogenic
13
Likely Pathogenic
180
VUS
93
Likely Benign
9
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
117
0
120
Likely Pathogenic
8
0
5
0
13
VUS
8
154
13
5
180
Likely Benign
0
2
30
61
93
Benign
0
1
3
5
9
Conflicting
—3
Total1815816871418

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

View in ClinVar →

Protein Context — Lollipop Plot

TBX6 · 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

Spondylocostal dysostosis 5

MIM #122600

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications.
Herlin MK·Front Endocrinol (Lausanne)
2024Review
Progress and perspective of TBX6 gene in congenital vertebral malformations.
Chen W et al.·Oncotarget
2016Review
Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine.
Zhao S et al.·Nat Commun
2024
TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.
Yang N et al.·Hum Mol Genet
2019
Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice.
Ren X et al.·J Med Genet
2020
Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome.
Ma C et al.·Genet Med
2022Functional
Functionally distinct roles for T and Tbx6 during mouse development.
Wehn AK et al.·Biol Open
2020Functional
TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.
Chen W et al.·Hum Mutat
2020
Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update.
Tewes AC et al.·Sex Dev
2019
Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China.
Feng X et al.·J Orthop Res
2021Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Dot1L Promotes Stress-Induced Cardiac Hypertrophy in Mice via Tbx6.
Liu J et al.·Circ Res
2025
Preliminary study assessing the long-term surgical outcomes of TBX6-associated congenital scoliosis (TACS) patients using the propensity score matching method: exploring the clinical implications of genetic discoveries in congenital scoliosis.
Lin G et al.·Orphanet J Rare Dis
2025🔓 Open AccessCohort
miR-1458 is inhibited by low concentrations of Vitamin B6 and targets TBX6 to promote the formation of spermatogonial stem cells in Rugao Yellow Chicken.
Geng Q et al.·Poult Sci
2025🔓 Open Access
Transcriptional regulation of olfactory receptor OR51B5 by the TBX6.
Roh J et al.·Am J Physiol Cell Physiol
2024
Concurrent of compound heterozygous variant of a novel in-frame deletion and the common hypomorphic haplotype in TBX6 and inherited 17q12 microdeletion in a fetus.
Li G et al.·BMC Pregnancy Childbirth
2024🔓 Open Access
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