TBX6

Chr 16ADAR

T-box transcription factor 6

Also known as: SCDO5

NCBI Gene: 6911ENSG00000149922UniProt: O95947OMIM: 602427

TBX6 encodes a T-box transcription factor that regulates axial stem cell fate determination between neural and mesodermal lineages and plays a role in left-right axis patterning during embryonic development. Mutations cause spondylocostal dysostosis 5, a vertebral segmentation disorder affecting the spine and ribs. Inheritance can be either autosomal dominant or autosomal recessive.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismAD/ARLOEUF 0.691 OMIM phenotype
Clinical Summary— TBX6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
135 unique Pathogenic / Likely Pathogenic· 180 VUS of 432 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — TBX6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

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

Typical tolerance to LoF variation

Missense Constraint
0.54Z-score
OE missense 0.91 (0.82–1.01)
254 obs / 279.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.37 (0.21–0.69)
0≤0.351.4
Missense OE0.91 (0.82–1.01)
0≤0.61.4
Synonymous OE0.98
0≤1.21.6
LoF obs/exp: 7 / 19.1Missense obs/exp: 254 / 279.2Syn Z: 0.17
DN
0.6649th %ile
GOF
0.4776th %ile
LOF
0.50top 25%

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

DNprediction above median
LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFComparative analysis of serum proteome in congenital scoliosis patients with TBX6 haploinsufficiency - a first report pointing to lipid metabolism.PMID:28944995

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

432 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic122
Likely Pathogenic13
VUS180
Likely Benign93
Benign9
Conflicting3
122
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
4
0
118
0
122
Likely Pathogenic
9
0
4
0
13
VUS
9
155
11
5
180
Likely Benign
0
2
30
61
93
Benign
0
1
3
5
9
Conflicting
—3
Total2215816671420

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.

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
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
2025Open 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
2025Open 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
2024Open Access
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