TBX4

Summary

TBX4 (T-box transcription factor 4, HGNC:11603) is a protein-coding gene on chromosome 17q23.2, encoding T-box transcription factor TBX4 (P57082). Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity.

Source: NCBI Gene 9496 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 361 total — 32 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 101
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001321120

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11603
Approved symbol	TBX4
Name	T-box transcription factor 4
Location	17q23.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000121075
Ensembl biotype	protein_coding
OMIM	601719
Entrez	9496

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000240335, ENST00000586874, ENST00000589003, ENST00000589449, ENST00000590174, ENST00000593249, ENST00000642491, ENST00000644296, ENST00000853300, ENST00000853301

RefSeq mRNA: 2 — MANE Select: NM_001321120 NM_001321120, NM_018488

CCDS: CCDS11629, CCDS82180

Canonical transcript exons

ENST00000644296 — 9 exons

Exon	Start	End
ENSE00001721574	61482897	61485110
ENSE00002245475	61456488	61456676
ENSE00003474616	61457537	61457631
ENSE00003486319	61465819	61465938
ENSE00003493125	61478627	61478779
ENSE00003528452	61480090	61480319
ENSE00003692012	61479881	61479969
ENSE00003693037	61467510	61467657
ENSE00003818532	61452422	61452577

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 92.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4720 / max 157.2595, expressed in 123 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162100	0.4513	120
162101	0.0208	10

Top tissues by expression

258 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	92.77	gold quality
upper lobe of left lung	UBERON:0008952	91.34	gold quality
upper lobe of lung	UBERON:0008948	89.76	gold quality
lung	UBERON:0002048	80.84	gold quality
calcaneal tendon	UBERON:0003701	75.39	gold quality
cartilage tissue	UBERON:0002418	73.83	gold quality
tibial artery	UBERON:0007610	70.19	gold quality
popliteal artery	UBERON:0002250	70.14	gold quality
lower lobe of lung	UBERON:0008949	69.05	silver quality
triceps brachii	UBERON:0001509	68.91	gold quality
gluteal muscle	UBERON:0002000	68.79	gold quality
diaphragm	UBERON:0001103	68.24	gold quality
parotid gland	UBERON:0001831	68.00	gold quality
urinary bladder	UBERON:0001255	65.74	gold quality
tendon	UBERON:0000043	65.27	gold quality
placenta	UBERON:0001987	65.18	gold quality
prostate gland	UBERON:0002367	62.88	gold quality
pancreatic ductal cell	CL:0002079	61.03	silver quality
decidua	UBERON:0002450	60.72	gold quality
aorta	UBERON:0000947	60.64	gold quality
heart right ventricle	UBERON:0002080	60.33	gold quality
gall bladder	UBERON:0002110	60.07	gold quality
secondary oocyte	CL:0000655	58.21	gold quality
right testis	UBERON:0004534	58.00	gold quality
deltoid	UBERON:0001476	57.98	gold quality
biceps brachii	UBERON:0001507	57.58	gold quality
myocardium	UBERON:0002349	57.39	gold quality
sural nerve	UBERON:0015488	56.97	gold quality
trabecular bone tissue	UBERON:0002483	56.95	gold quality
quadriceps femoris	UBERON:0001377	56.52	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
FGF10
GNG3
PPIG
UGT1A1

JASPAR motifs

Motif	Name	Family
MA0806.1	TBX4	TBX2-related factors

JASPAR matrix evidence (PMIDs): PMID:12093383

Upstream regulators (CollecTRI, top): PITX1

miRNA regulators (miRDB)

68 targeting TBX4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-142-3P	99.62	71.30	974

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• Mutations in the human TBX4 gene cause small patella syndrome (PMID:15106123)
• Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. (PMID:21271665)
• a low level of TBX4 expression suggests a worse prognosis for patients with stage II PDAC. Down-regulation of the TBX4 gene in pancreas is less likely to be regulated by DNA methylation. (PMID:21954337)
• Minimal evidence was found for an association between TBX4 and clubfoot and no pathogenic sequence variants were identified in the two known TBX4 hindlimb enhancer elements. (PMID:22678995)
• data indicate that TBX4 mutations are associated with childhood-onset pulmonary arterial hypertension (PAH), but the prevalence of PAH in adult TBX4 mutation carriers is low (PMID:23592887)
• Although TBX4 remains the candidate gene for congenital clubfoot involving 17q23.1-q23.2 duplications, the explanation for variable expressivity and penetrance remains unknown. (PMID:24592505)
• We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. (PMID:27374786)
• TBX4 is a mesenchymal transcription factor that drives accumulation of myofibroblasts and the development of lung fibrosis (PMID:27400124)
• In a cohort with idiopathic or hereditary pulmonary arterial hypertension, a possibly associated mutation was found in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases. There were 4 mutations found in TBX4. (PMID:27453251)
• highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis (PMID:28971975)
• In seven families we foundTBX4anomalies predictedto cause loss-of-function or haploinsufficiency, confirming the clinicaldiagnosis of Small patella syndrome (PMID:29120062)
• The results suggested that rs6557421 variant in Nox3 and rs3744439 variant in Tbx4 might have potential effect on individual susceptibility to pulmonary hypertension. (PMID:30290780)
• Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases. (PMID:30578383)
• Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway (PMID:30639323)
• Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension. (PMID:31151956)
• Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia. (PMID:31761294)
• Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation. (PMID:32079640)
• TBX4 variants and pulmonary diseases: getting out of the ‘Box’. (PMID:32195678)
• We present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. (PMID:32348326)
• Rare and de novo duplications containing SHOX in clubfoot. (PMID:32518174)
• Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients. (PMID:33066286)
• Potential interactions between the TBX4-FGF10 and SHH-FOXF1 signaling during human lung development revealed using ChIP-seq. (PMID:33478486)
• Identification and Functional Evaluation of a Novel TBX4 Mutation Underlies Small Patella Syndrome. (PMID:35216193)
• What Is the Exact Contribution of PITX1 and TBX4 Genes in Clubfoot Development? An Italian Study. (PMID:36360195)
• Long-Term Effect of TBX4 Germline Mutation on Pulmonary Clinico-Histopathologic Phenotype. (PMID:37801629)
• Computed tomographic findings in TBX4 mutation: a common cause of severe pulmonary artery hypertension in children. (PMID:38191808)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx4	ENSDARG00000030058
mus_musculus	Tbx4	ENSMUSG00000000094
rattus_norvegicus	Tbx4	ENSRNOG00000003544
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX4 — P57082 (reviewed: P57082)

All UniProt accessions (2): P57082, K7EPY2

UniProt curated annotations — full annotation on UniProt →

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

Subcellular location. Nucleus.

Disease relevance. Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS) [MIM:147891] An autosomal dominant bone disease characterized by patellar aplasia or hypoplasia and by anomalies of the pelvis and feet, including disrupted ossification of the ischia and inferior pubic rami. The disease is caused by variants affecting the gene represented in this entry. Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome (PAPPAS) [MIM:601360] An autosomal recessive, lethal embryonic syndrome characterized by absent hindlimbs, pulmonary hypoplasia, severely hypoplastic or absent pelvic bones, hypoplasia of the sacrum, and ambiguous genitalia. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
P57082-1	1	yes
P57082-2	2

RefSeq proteins (2): NP_001308049, NP_060958 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (13 total): sequence variant 7, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57082-F1	60.96	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 507

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 347 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, HNF3ALPHA_Q6, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_HINDLIMB_MORPHOGENESIS, FOXO4_01, FOXO1_01, USF_C, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, FREAC3_01, GATA6_01, GOBP_APPENDAGE_DEVELOPMENT, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_EMBRYONIC_HINDLIMB_MORPHOGENESIS

GO Biological Process (12): angiogenesis (GO:0001525), cell fate specification (GO:0001708), morphogenesis of an epithelium (GO:0002009), regulation of transcription by RNA polymerase II (GO:0006357), lung development (GO:0030324), limb morphogenesis (GO:0035108), embryonic hindlimb morphogenesis (GO:0035116), positive regulation of DNA-templated transcription (GO:0045893), skeletal system morphogenesis (GO:0048705), embryonic lung development (GO:1990401), regulation of DNA-templated transcription (GO:0006355), embryonic limb morphogenesis (GO:0030326)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell fate commitment	1
cellular developmental process	1
tissue morphogenesis	1
epithelium development	1
transcription by RNA polymerase II	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
appendage morphogenesis	1
limb development	1
embryonic limb morphogenesis	1
hindlimb morphogenesis	1
positive regulation of RNA biosynthetic process	1
skeletal system development	1
animal organ morphogenesis	1
embryonic organ development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1044 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX4	PITX1	P78337	921
TBX4	HOXC10	Q9NYD6	902
TBX4	HOXC11	O43248	842
TBX4	FGF10	O15520	729
TBX4	BCAS3	Q9H6U6	697
TBX4	PDLIM7	Q9NR12	679
TBX4	LMX1B	O60663	674
TBX4	ATP13A3	Q9H7F0	665
TBX4	KCNK3	O14649	629
TBX4	PITX2	Q99697	606
TBX4	NKX2-5	P52952	599
TBX4	BMPR2	Q13873	594
TBX4	ACVRL1	P37023	586
TBX4	SALL4	Q9UJQ4	576
TBX4	GDF5	P43026	561

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TBX4	TENT5A	psi-mi:“MI:0915”(physical association)	0.370
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): TBX4 (Proximity Label-MS), TBX4 (Synthetic Lethality), TBX4 (Proximity Label-MS), TBX4 (Affinity Capture-MS), TBX4 (Two-hybrid)

ESM2 similar proteins: A0PJS5, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A3KNJ3, A7Y7W3, A8K830, F6W2R2, F8VPY8, O15353, O42506, O43186, O54751, P14653, P17919, P28322, P31276, P32243, P40646, P43268, P57082, P70056, P80206, P83758, Q00288, Q06710, Q08820, Q16633, Q1KL10, Q28GC4, Q28IU6, Q2KJA4, Q4G112, Q503Z8, Q64693, Q66IK1, Q66IT9, Q7T1C0

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

361 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	30
Uncertain significance	152
Likely benign	35
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1341404	NM_001321120.2(TBX4):c.781C>T (p.Arg261Ter)	Pathogenic
1341420	NM_001321120.2(TBX4):c.1167dup (p.Arg390fs)	Pathogenic
1341425	NM_001321120.2(TBX4):c.64G>T (p.Gly22Ter)	Pathogenic
1341439	NM_001321120.2(TBX4):c.379T>A (p.Tyr127Asn)	Pathogenic
1341445	NM_001321120.2(TBX4):c.748C>T (p.Arg250Trp)	Pathogenic
1341452	NM_001321120.2(TBX4):c.985G>T (p.Asp329Tyr)	Pathogenic
1454188	NM_001321120.2(TBX4):c.994del (p.Leu332fs)	Pathogenic
1456638	NC_000017.10:g.(?59533852)(59560877_?)del	Pathogenic
1965499	NM_001321120.2(TBX4):c.934C>T (p.Gln312Ter)	Pathogenic
2035507	NM_001321120.2(TBX4):c.721G>T (p.Glu241Ter)	Pathogenic
2799754	NM_001321120.2(TBX4):c.847C>T (p.Gln283Ter)	Pathogenic
2825071	NM_001321120.2(TBX4):c.593del (p.Ile198fs)	Pathogenic
2857352	NM_001321120.2(TBX4):c.571A>T (p.Lys191Ter)	Pathogenic
3061910	NM_001321120.2(TBX4):c.549+1G>A	Pathogenic
3243199	NC_000017.10:g.(?59544851)(59545038_?)del	Pathogenic
3243200	NC_000017.10:g.(?59543160)(59545038_?)del	Pathogenic
3652480	NM_001321120.2(TBX4):c.1427_1430dup (p.Leu478fs)	Pathogenic
3900700	NM_001321120.2(TBX4):c.1104_1107dup (p.Ser370fs)	Pathogenic
450470	NM_001321120.2(TBX4):c.709C>T (p.Gln237Ter)	Pathogenic
452418	NM_001321120.2(TBX4):c.281+1G>A	Pathogenic
4730186	NM_001321120.2(TBX4):c.1100_1101dup (p.Phe368fs)	Pathogenic
620312	NM_001321120.2(TBX4):c.1018C>T (p.Arg340Ter)	Pathogenic
633610	NM_001321120.2(TBX4):c.355dup (p.Ile119fs)	Pathogenic
638159	NM_001321120.2(TBX4):c.402G>A (p.Trp134Ter)	Pathogenic
7855	NM_001321120.2(TBX4):c.743G>T (p.Gly248Val)	Pathogenic
7856	NM_001321120.2(TBX4):c.184C>T (p.Gln62Ter)	Pathogenic
7857	NM_001321120.2(TBX4):c.1595A>G (p.Gln532Arg)	Pathogenic
800703	NM_001321120.2(TBX4):c.251del (p.Gly84fs)	Pathogenic
805945	NM_001321120.2(TBX4):c.339T>A (p.Tyr113Ter)	Pathogenic
807511	NM_001321120.2(TBX4):c.281+1G>T	Pathogenic

SpliceAI

1291 predictions. Top by Δscore:

Variant	Effect	Δscore
17:61465774:T:TA	acceptor_gain	1.0000
17:61465790:C:G	acceptor_gain	1.0000
17:61465936:ATGG:A	donor_loss	1.0000
17:61465937:TGG:T	donor_loss	1.0000
17:61465939:GT:G	donor_loss	1.0000
17:61465940:T:A	donor_loss	1.0000
17:61467504:T:A	acceptor_gain	1.0000
17:61467505:GGCA:G	acceptor_loss	1.0000
17:61467506:GCA:G	acceptor_loss	1.0000
17:61467507:CA:C	acceptor_loss	1.0000
17:61467508:AG:A	acceptor_gain	1.0000
17:61467508:AGG:A	acceptor_loss	1.0000
17:61467508:AGGAT:A	acceptor_gain	1.0000
17:61467509:GG:G	acceptor_gain	1.0000
17:61467509:GGA:G	acceptor_gain	1.0000
17:61467509:GGATG:G	acceptor_gain	1.0000
17:61467653:GCCAT:G	donor_gain	1.0000
17:61467658:G:GG	donor_gain	1.0000
17:61478622:TCCA:T	acceptor_loss	1.0000
17:61478623:CCAG:C	acceptor_loss	1.0000
17:61478624:CA:C	acceptor_loss	1.0000
17:61478625:A:AG	acceptor_gain	1.0000
17:61478625:A:T	acceptor_loss	1.0000
17:61478626:G:GA	acceptor_gain	1.0000
17:61478626:GA:G	acceptor_gain	1.0000
17:61478626:GAT:G	acceptor_gain	1.0000
17:61478626:GATC:G	acceptor_gain	1.0000
17:61478626:GATCA:G	acceptor_gain	1.0000
17:61478776:CAAGG:C	donor_loss	1.0000
17:61478780:G:GG	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000024485 (17:61476550 C>T), RS1000108198 (17:61470789 C>A), RS1000313594 (17:61476570 C>T), RS1000320411 (17:61465214 C>A,G,T), RS1000397578 (17:61459335 C>T), RS1000409043 (17:61458991 T>C), RS1000475074 (17:61481261 T>G), RS1000507548 (17:61480398 C>A,G,T), RS1000625971 (17:61460329 G>A), RS1000728625 (17:61460857 A>G), RS1000801060 (17:61482010 G>A,T), RS1000854803 (17:61481723 G>A,T), RS1000935693 (17:61476012 C>T), RS1001006117 (17:61459636 A>C), RS1001067675 (17:61485496 G>A)

Disease associations

OMIM: gene MIM:601719 | disease phenotypes: MIM:147891, MIM:178600, MIM:265430, MIM:601360, MIM:241550

GenCC curated gene-disease

Disease	Classification	Inheritance
coxopodopatellar syndrome	Definitive	Autosomal dominant
autosomal recessive amelia	Strong	Semidominant
heritable pulmonary arterial hypertension	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pulmonary arterial hypertension	Definitive	AD

Mondo (9): coxopodopatellar syndrome (MONDO:0007841), pulmonary hypertension, primary, 1 (MONDO:0024533), familial primary pulmonary hypoplasia (MONDO:0009936), autosomal recessive amelia (MONDO:0011054), hypoplastic left heart syndrome (MONDO:0004933), hydronephrosis (MONDO:0005510), pulmonary hypoplasia (MONDO:0800133), pulmonary arterial hypertension (MONDO:0015924), heritable pulmonary arterial hypertension (MONDO:0017148)

Orphanet (7): Coxopodopatellar syndrome (Orphanet:1509), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Primary pulmonary hypoplasia (Orphanet:2257), Autosomal recessive amelia (Orphanet:1027), Pulmonary arterial hypertension associated with congenital heart disease (Orphanet:275803), Hypoplastic left heart syndrome (Orphanet:2248), Pulmonary arterial hypertension (Orphanet:182090)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000049	Shawl scrotum
HP:0000148	Vaginal atresia
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000498	Blepharitis
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0000648	Optic atrophy

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000175_44	Height	6.000000e-08
GCST000522_6	Height	3.000000e-06
GCST002702_101	Height	2.000000e-17
GCST002932_4	Manganese levels	6.000000e-06
GCST003265_439	Post bronchodilator FEV1/FVC ratio in COPD	9.000000e-07
GCST004796_2	Brain volume in infants (cerebrospinal fluid)	5.000000e-07
GCST006979_512	Heel bone mineral density	1.000000e-15
GCST008161_20	Waist circumference adjusted for body mass index	6.000000e-06
GCST008163_406	Height	2.000000e-06
GCST008280_2	Intertrochanteric region size	5.000000e-09
GCST008281_3	Hip bone size	3.000000e-09
GCST008839_431	Height	1.000000e-61
GCST90007000_11	Gut microbiota relative abundance (unclassified genus belonging to family Ruminococcaceae)	1.000000e-07
GCST90013466_20	Height	9.000000e-10
GCST90013466_39	Height	2.000000e-13
GCST90013467_8	Height	7.000000e-08
GCST90013468_5	Height	5.000000e-08
GCST90020028_1426	Hip circumference adjusted for BMI	1.000000e-08
GCST90020029_493	Waist circumference adjusted for body mass index	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0009270	heel bone mineral density
EFO:0007789	BMI-adjusted waist circumference
EFO:0010075	intertrochanteric region size
EFO:0007874	gut microbiome measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D006869	Hydronephrosis	C12.050.351.968.419.307; C12.200.777.419.307; C12.950.419.307
D018636	Hypoplastic Left Heart Syndrome	C14.240.400.625; C14.280.400.625; C16.131.240.400.625
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
C563338	Amelia, Autosomal Recessive (supp.)
C535540	Ischiopatellar dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	2
Asbestos, Crocidolite	decreases methylation	2
OTX015	decreases expression	1
mivebresib	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Leflunomide	increases expression	1
Microplastics	increases abundance, decreases expression	1
Amiodarone	increases expression	1
Cadmium	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polystyrenes	decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Amosite	decreases methylation	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8L6	SEES3-1V human TBX4, clone1	Embryonic stem cell	Male
CVCL_A8L7	SEES3-1V human TBX4, clone2	Embryonic stem cell	Male
CVCL_A8L8	SEES3-1V human TBX4, clone3	Embryonic stem cell	Male
CVCL_F0YK	GM29205	Transformed cell line	Male
CVCL_F0YQ	GM29333	Transformed cell line	Male

Clinical trials (associated diseases)

304 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial