TBX4

Chr 17ARAD

T-box transcription factor 4

NCBI Gene: 9496 ENSG00000121075 UniProt: P57082 OMIM: 601719

TBX4 encodes a transcriptional regulator essential for organogenesis of lungs, pelvis, and hindlimbs. Mutations cause small patella syndrome and infantile pulmonary arterial hypertension, both inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.445), reflecting its critical developmental role.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Amelia, posterior, with pelvic and pulmonary hypoplasia syndromeMIM #601360

Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertensionMIM #147891

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · pulmonary arterial hypertension · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.45

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TBX4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

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?

0.87Z-score

OE missense 0.86 (0.78–0.95)

269 obs / 312.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.11–0.45)

0≤0.351.4

Missense OE?0.86 (0.78–0.95)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 5 / 23.6Missense obs/exp: 269 / 312.3Syn Z: -0.69

Background carrier burden — how many people carry a rare variant somewhere in TBX4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 78

675 rare PASS variants

Rare truncating (LoF)

1 in 2,900

36 rare PASS variants

Rare synonymous (reference)

1 in 84

333 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBX4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 98	1 in 3,000
South Asian	~43k	1 in 79	1 in 4,100
Remaining (unassigned)	~30k	1 in 97	1 in 5,800
European (Finnish)	~27k	1 in 120	1 in 3,800
Admixed American	~22k	1 in 85	1 in 1,900
African / African American	~21k	1 in 74	1 in 1,400
East Asian	~20k	1 in 100	none seen
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 120	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 8.? see exons ↓