TBX18

Chr 6AD

T-box transcription factor 18

Also known as: CAKUT2, PUJO

NCBI Gene: 9096ENSG00000112837UniProt: O95935OMIM: 604613

TBX18 encodes a transcription factor that acts as a transcriptional repressor essential for embryonic development of multiple organ systems, including the heart (particularly the sinoatrial node), coronary vessels, ureter, and vertebral column. Mutations cause autosomal dominant congenital anomalies of the kidney and urinary tract, and the gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.19), indicating that such mutations are likely to have severe developmental consequences.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismADLOEUF 0.191 OMIM phenotype
Clinical Summary— TBX18
⚡
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
18 unique Pathogenic / Likely Pathogenic· 158 VUS of 278 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.19LOEUF
pLI 0.999
Z-score 4.41
OE 0.04 (0.01–0.19)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
0.10Z-score
OE missense 0.98 (0.90–1.08)
336 obs / 341.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.04 (0.01–0.19)
0≤0.351.4
Missense OE0.98 (0.90–1.08)
0≤0.61.4
Synonymous OE0.85
0≤1.21.6
LoF obs/exp: 1 / 24.6Missense obs/exp: 336 / 341.1Syn Z: 1.37
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongTBX18-related congenital anomalies of kidney and urinary tractLOFAD
DN
0.4289th %ile
GOF
0.2994th %ile
LOF
0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). 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 · 22% of P/LP variants are LoF · LOEUF 0.19
DN1 literature citation

Literature Evidence

DNThese data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.PMID:26235987

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

278 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic3
VUS158
Likely Benign66
Benign22
Conflicting5
15
Pathogenic
3
Likely Pathogenic
158
VUS
66
Likely Benign
22
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
12
0
15
Likely Pathogenic
2
1
0
0
3
VUS
6
142
10
0
158
Likely Benign
0
9
14
43
66
Benign
0
3
15
4
22
Conflicting
—5
Total101565147269

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

View in ClinVar →

Protein Context — Lollipop Plot

TBX18 · 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