TBX4

Chr 17ARAD

T-box transcription factor 4

ENSG00000121075UniProt: P57082

Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs

Primary Disease Associations & Inheritance

Amelia, posterior, with pelvic and pulmonary hypoplasia syndromeMIM #601360
AR
Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertensionMIM #147891
AD
1
Active trials
66
Pathogenic / LP
260
ClinVar variants
6
Pubs (1 yr)
0.9
Missense Z
0.45
LOEUF
Clinical Summary— TBX4
🧬
Gene-Disease Validity (ClinGen)
pulmonary arterial hypertension · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.50) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
66 Pathogenic / Likely Pathogenic· 102 VUS of 260 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — TBX4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

ncbi: TypeError: fetch failed

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.
0.45LOEUF
pLI 0.505
Z-score 3.55
OE 0.21 (0.11–0.45)
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.
0.87Z-score
OE missense 0.86 (0.78–0.95)
269 obs / 312.3 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.0.21 (0.11–0.45)
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 (0.78–0.95)
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.1.08
0≤1.21.6
LoF obs/exp: 5 / 23.6Missense obs/exp: 269 / 312.3Syn Z: -0.69
DN
0.5575th %ile
GOF
0.3887th %ile
LOF
0.69top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 39% of P/LP variants are LoF · LOEUF 0.45

Literature Evidence

LOFMutations in the human TBX4 gene cause small patella syndromePMID:15106123

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

260 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic29
VUS102
Likely Benign36
Benign45
Conflicting11
37
Pathogenic
29
Likely Pathogenic
102
VUS
36
Likely Benign
45
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
2
25
0
37
Likely Pathogenic
16
2
11
0
29
VUS
2
81
14
5
102
Likely Benign
0
8
6
22
36
Benign
0
5
31
9
45
Conflicting
—11
Total28988736260

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

View in ClinVar →

Protein Context — Lollipop Plot

TBX4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TBX4-related ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

TBX4-related posterior amelia with pelvic and pulmonary hypoplasia

limited
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

Clinical Literature
Landmark / reviewRecent case evidence
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
Generation of 5 hiPSC lines from pediatric patients with Heritable pulmonary arterial hypertension (HPAH) caused by heterozygous mutations in the TBX4 gene.
Fernandez Vallone V et al.·Stem Cell Res
2026Cohort
Loss of Tbx4 Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension.
Maldonado-Velez G et al.·Am J Respir Cell Mol Biol
2025
Pulmonary Arterial Hypertension Onset in an Adult Woman With a TBX4 Likely Pathogenic Variant Following Imatinib Administration: A Case Report.
Carbonera S et al.·Am J Med Genet A
2025Case report
Highly Variable Expressivity of a CNV Deletion Involving TBX4 in Three Deceased Siblings With Lung Developmental Disorder and Their Mildly Affected Mother and Grandfather.
Szafranski P et al.·Clin Genet
2026
Postnatally induced TBX4 insufficiency confers pulmonary hypertension and impairs lung development in infant mice.
Smith CF et al.·Pediatr Res
2026
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