SMAD6

Summary

SMAD6 (SMAD family member 6, HGNC:6772) is a protein-coding gene on chromosome 15q22.31, encoding SMAD family member 6 (O43541). Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.

The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila ‘mothers against decapentaplegic’ (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.

Source: NCBI Gene 4091 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SMAD6-related disease (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 32
• Clinical variants (ClinVar): 1,331 total — 41 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 26
• Transcription factor: yes — 25 downstream targets (CollecTRI)
• MANE Select transcript: NM_005585

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6772
Approved symbol	SMAD6
Name	SMAD family member 6
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	HsT17432
Ensembl gene	ENSG00000137834
Ensembl biotype	protein_coding
OMIM	602931
Entrez	4091

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000288840, ENST00000557916, ENST00000558937, ENST00000559931, ENST00000612349, ENST00000922587, ENST00000966143

RefSeq mRNA: 1 — MANE Select: NM_005585 NM_005585

CCDS: CCDS10221

Canonical transcript exons

ENST00000288840 — 4 exons

Exon	Start	End
ENSE00000931633	66711668	66711724
ENSE00000931634	66716421	66716498
ENSE00001857554	66780997	66782849
ENSE00001955815	66702236	66704075

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7518 / max 122.4586, expressed in 1374 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147279	2.4948	1044
147281	2.3104	997
147280	1.0384	588
147282	0.3038	174
147278	0.2501	116
147283	0.2363	118
147285	0.0935	43
147284	0.0244	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	97.84	gold quality
renal glomerulus	UBERON:0000074	95.60	gold quality
metanephric glomerulus	UBERON:0004736	95.26	gold quality
lower lobe of lung	UBERON:0008949	94.85	gold quality
right atrium auricular region	UBERON:0006631	93.09	gold quality
cardiac atrium	UBERON:0002081	92.66	gold quality
upper lobe of lung	UBERON:0008948	91.55	gold quality
upper lobe of left lung	UBERON:0008952	91.50	gold quality
visceral pleura	UBERON:0002401	90.94	gold quality
choroid plexus epithelium	UBERON:0003911	90.39	gold quality
right lobe of thyroid gland	UBERON:0001119	89.95	gold quality
lung	UBERON:0002048	89.70	gold quality
pigmented layer of retina	UBERON:0001782	89.53	gold quality
retina	UBERON:0000966	89.51	gold quality
metanephros	UBERON:0000081	89.34	gold quality
right coronary artery	UBERON:0001625	88.60	gold quality
left lobe of thyroid gland	UBERON:0001120	87.81	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.77	gold quality
kidney epithelium	UBERON:0004819	87.29	gold quality
popliteal artery	UBERON:0002250	87.27	gold quality
tibial artery	UBERON:0007610	87.25	gold quality
left coronary artery	UBERON:0001626	87.07	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	86.78	gold quality
thyroid gland	UBERON:0002046	86.76	gold quality
heart	UBERON:0000948	86.73	gold quality
coronary artery	UBERON:0001621	86.73	gold quality
aorta	UBERON:0000947	86.61	gold quality
periodontal ligament	UBERON:0008266	86.58	gold quality
myocardium	UBERON:0002349	86.38	gold quality
cortex of kidney	UBERON:0001225	86.32	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	463.94
E-ANND-3	yes	13.06

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

25 targets.

Target	Regulation
ANKRD1	Repression
CDK6	Repression
CDKN1A	Repression
COL10A1	Repression
COL1A2
DLX3
ESX1	Repression
FGFR1
FOXD1	Unknown
KLF1
KRAS
KRT27
ME3
PCK2	Repression
PPARG	Repression
PROC	Repression
PROM1	Repression
RB1	Repression
SERPINE1	Repression
SMAD1
SMAD6
TAGLN	Repression
TBX6	Unknown
TNFRSF11B	Repression
WDR5	Repression

Upstream regulators (CollecTRI, top): CREB1, HOXC8, RUNX1, RUNX2, SMAD1, SMAD5, SMAD6

miRNA regulators (miRDB)

88 targeting SMAD6, 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-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-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-767-5P	99.95	70.85	993

Literature-anchored findings (GeneRIF, showing 40)

• Smad6 has no role in TGF-beta response and injury in podocytes. In contrast, Smad6 is upregulated in the mesangium in human glomerular diseases and may be involved in functions independent of TGF-beta/Smad signaling. (PMID:12397035)
• Smad6 and Smad7 regulate thrombomodulin-dependent activation of protein C (PMID:12407115)
• Smad6 repressed bone morphogenetic protein-induced Id1 transcription through recruiting transcriptional corepressor C-terminal binding protein (CtBP). (PMID:14645520)
• tetradecanoylphorbol-13-acetate down-regulates Smad6 expression presumably via PKCmu-ERK-dependent pathway and up-regulates Smad7 expression via PKCmu-dependent mechanism(s) which need no MAPK and NF-kappaB activation (PMID:15033458)
• The regulation in chondrocytes of Smad6 and Smad7 expression by IL-1beta suggests a potentially important role of IL-1beta signaling in chondrocytes, via indirect influencing of the bone morphogenetic protein/TGFbeta signaling cascade. (PMID:15529348)
• Adrenomedullin can attenuate TGF-beta1-mediated renal tubulointerstitial extracellular matrix turnover via an antagonistic mechanism of inhibitory Smad 6 in TGF-beta1-elicited signaling. (PMID:15665522)
• the level of Smad6s can alter the level of TGF-beta and the subsequent induction of PAI-1 via a FoxD1 transcription site (PMID:15716278)
• Smad6 and Smad7 expression affects the progression of early lesions of esophageal SCC and indicates a poor prognosis. (PMID:15736400)
• appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGFbeta family of proteins (PMID:16249187)
• Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation (PMID:16299379)
• OAZ can alter the intensity and duration of the BMP4 stimulus through Smad6 (PMID:16373339)
• Smad6 appears to functionally interact with Dlx3, altering the ability of Dlx3 to bind target gene promoters. (PMID:16687405)
• Smad6 bound to Pellino-1 promoted TGF-beta-mediated anti-inflammatory effects. (PMID:16951688)
• These data suggest autocrine TGF-beta1 antagonizes BMP signaling through modulation of inducible Smad6 and the activity of BMP specific Smad1/5. (PMID:17359969)
• Stimulation of Smad 6 inhibits ERK activation and thus results in a negative feedback loop to fine-tune BMP signaling in human umbilical vein endothelial cells. (PMID:17850776)
• A case-control study in Afro-Caribbeans found SMAD6 SNPs were not strongly associated with increased risk of developing keloids. (PMID:18445023)
• Splice variant Smad6B, in human prostatic and rodent testicular cell lines, exhibits a truncated C-terminus lacking the entire MH-2 domain and most parts of the linker region. (PMID:19032685)
• Knockdown of SMAD6 led to the activation of TGF-beta signaling through up-regulation of plasminogen activator inhibitor-1 and phosphorylation of SMAD2/3 in NSCLC. (PMID:19047146)
• Smad6 gene is a candidate for the genetic determinants of bone mineral density in postmenopausal women. (PMID:19277452)
• Study data demonstrates downregulated SMAD6 expression in psoriatic skin. (PMID:19688145)
• Smad6 together with Smad2 may be prognostic factors, independent of nodal status in oral SCC after curative resection (PMID:20462450)
• Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-mutant hereditary hemochromatosis compared to controls, disruptin bone morphogenic protein signaling. (PMID:20658468)
• Data show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros region in the developing embryo, where hematopoietic stem cells originate. (PMID:21576367)
• results suggest that MyD88 degradation driven by the Smad6-Smurf pathway is a novel mechanism for TGF-beta1-mediated negative regulation of MyD88-dependent pro-inflammatory signalling (PMID:21897371)
• Haplotype analysis further revealed that two haplotype blocks within SMAD6 were significantly associated with decreased ovarian cancer risk, as compared to the most common haplotype. (PMID:21984931)
• Loss of SMAD6 is associated with lung adenocarcinoma. (PMID:22223368)
• Congenital cardiovascular malformation is related to genetic variation in SMAD6 (PMID:22275001)
• Smad6 indirectly maintains stemness by preventing spontaneous erythropoiesis in hematopoietic stem cells. (PMID:22705548)
• Single Nucleotide Polymorphisms in SMAD6 gene is associated with brain metastasis in non-small-cell lung cancer (PMID:23284751)
• monoubiquitinated SMAD6 impairs the binding affinity of non-modified SMAD6 to the BMP type I receptor. Moreover, UBE2O and SMAD6 cooperated in the regulation of BMP7-induced adipogenesis (PMID:23455153)
• Results show that high Smad6 expression is correlated with increased risk of metastasis in ER negative breast cancer and that Smad6 determines BMP-regulated invasive behavior of breast cancer cells in a zebrafish xenograft model. (PMID:27113436)
• This search revealed that rare mutations that disable one copy of a gene called SMAD6 in combination with a common DNA variant near another gene called BMP2 account for about 7% of infants with midline forms of craniosynostosis. (PMID:27606499)
• activation of AMPK upregulated Smad6 and Smurf1 and thereby enhanced their interactions, resulting in its proteosome-dependent degradation of ALK2. (PMID:28847510)
• evaluated the role of inherited genetic variation in Langerhans cell histiocytosis susceptibility and identified a novel risk variant in SMAD6 (PMID:28935696)
• Overexpression of miR186 mimic induced HUVEC apoptosis through mitogenactivated protein kinase (MAPK) activation by targeting and inhibiting SMAD family member 6 (SMAD6). (PMID:29344637)
• SMAD6 overexpression leads to accelerated myogenic differentiation of LMNA mutated cells. (PMID:29618840)
• Study reports that SMAD6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating PIAS3. Mechanically, SMAD6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 domain of SMAD6 and the Ring domain of PIAS3. (PMID:29950561)
• data provide improved insights into the clinical spectrum of SMAD6-related bicuspid aortic valve/thoracic aortic aneurysm and has important implications for molecular diagnostics. (PMID:30796334)
• A novel SMAD6 variant was identified in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm. (PMID:30848080)
• Data indicate two individuals with biallelic missense variants in SMAD6 and a complex cardiac phenotype. (PMID:30963242)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	smad6b	ENSDARG00000031763
danio_rerio	smad6a	ENSDARG00000053209
mus_musculus	Smad6	ENSMUSG00000036867
rattus_norvegicus	Smad6	ENSRNOG00000009173
caenorhabditis_elegans		WBGENE00000910

Paralogs (7): SMAD7 (ENSG00000101665), SMAD5 (ENSG00000113658), SMAD9 (ENSG00000120693), SMAD4 (ENSG00000141646), SMAD3 (ENSG00000166949), SMAD1 (ENSG00000170365), SMAD2 (ENSG00000175387)

Protein

Protein identifiers

SMAD family member 6 — O43541 (reviewed: O43541)

Alternative names: Mothers against decapentaplegic homolog 6

All UniProt accessions (3): O43541, H0YK80, H0YM33

UniProt curated annotations — full annotation on UniProt →

Function. Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-beta. Acts as a mediator of TGF-beta and BMP anti-inflammatory activities. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of pro-inflammatory genes. Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions.

Subunit / interactions. Interacts with NEDD4L. Interacts with WWP1. Interacts with STAMBP and PRKX. Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, including ACVR1B, BMPR1B and TGFBR1. In response to BMP2, but not to TGFB treatment, interacts with SMAD1, but not with SMAD2, nor with SMAD4; this interaction may inhibit SMAD1 binding to SMAD4. Interacts with HOXC8 and HOXC9. Interacts with PELI1; this interaction interferes with PELI1 complex formation with TRAF6, IRAK1, IRAK4 and MYD88 in response to IL1B and hence negatively regulates IL1R-TLR signaling. Interacts with TSC22D1/TSC-22.

Subcellular location. Nucleus.

Tissue specificity. Expressed in the brain, heart, ovary, peripheral blood leukocytes, small intestine, spleen, thymus, bone marrow, fetal liver and lymph nodes.

Post-translational modifications. Phosphorylated by BMP type 1 receptor kinase and by PRKX. Monoubiquitinated at Lys-173 by the E2/E3 hybrid ubiquitin-protein ligase UBE2O, leading to reduced binding affinity for the activated BMP type I receptor ACVR1/ALK2, thereby enhancing BMP7 and regulating adipocyte differentiation. Ubiquitinated by WWP1. Ubiquitinated by ARK2C, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling. Arginine methylation by PRMT1, which is recruited by BMPR2, initiates BMP-Induced signaling and induces dissociation from the BMPR1B receptor at the cell surface leading to derepress downstream Smad1/Smad5 signaling.

Disease relevance. Aortic valve disease 2 (AOVD2) [MIM:614823] A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. The disease is caused by variants affecting the gene represented in this entry. SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility. Craniosynostosis 7 (CRS7) [MIM:617439] A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. Disease susceptibility is associated with variants affecting the gene represented in this entry. Rare heterozygous SMAD6 variants have been reported to be strongly associated with non-syndromic midline craniosynostosis, confering a very high risk for disease development in the presence of a common risk allele (rs1884302) near the BMP2 locus. The modifier role of rs1884302 SNP on craniosynostosis development associated with SMAD6 variants has not been confirmed in further studies. Radioulnar synostosis, non-syndromic (RUS) [MIM:179300] An autosomal dominant disease characterized by proximal fusion of the radius and ulna resulting in extremely limited pronation and supination of the forearm. There are two disease forms. Radioulnar synostosis type 1 is characterized by a proximal fusion between the radius and ulna, and the radial head is absent. Radioulnar synostosis type 2 is characterized by a fusion just distal to the proximal radial epiphysis, and congenital dislocation of the radial head. In radioulnar synostosis type 2 there is also a restriction of extension at the elbow. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the dwarfin/SMAD family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43541-1	A	yes
O43541-2	B, Smad 6S
O43541-4	D

RefSeq proteins (1): NP_005576* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001132	SMAD_dom	Domain
IPR003619	MAD_homology1_Dwarfin-type	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR013019	MAD_homology_MH1	Domain
IPR013790	SMAD/Dwarfins	Family
IPR017855	SMAD-like_dom_sf	Homologous_superfamily
IPR036578	SMAD_MH1_sf	Homologous_superfamily

Pfam: PF03165, PF03166

UniProt features (79 total): sequence variant 54, modified residue 5, splice variant 4, binding site 4, mutagenesis site 4, domain 2, region of interest 2, chain 1, cross-link 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43541-F1	72.34	0.48

Functional residue map

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

Ligand- & substrate-binding residues (4): 205; 247; 260; 265

Post-translational modifications (6): 75, 75, 82, 82, 435, 173

Mutagenesis-validated functional residues (4):

Position	Phenotype
173	abolishes monoubiquitination by ube2o.
435	loss of in vitro phosphorylation by prkx.
471	loss of smad1-binding and of inhibition of bmp-smad1 signaling. no effect on interaction with bmpr1b and tgfbr1.
478–496	loss of interaction with bmpr1b, tgfbr1 and smad1.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-8941326	RUNX2 regulates bone development
R-HSA-162582	Signal Transduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 463 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, E2F_Q4, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_AXIS_SPECIFICATION, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, E2F4DP1_01, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_EMBRYONIC_AXIS_SPECIFICATION, NKX25_02

GO Biological Process (34): ureteric bud development (GO:0001657), outflow tract septum morphogenesis (GO:0003148), aortic valve morphogenesis (GO:0003180), mitral valve morphogenesis (GO:0003183), pulmonary valve morphogenesis (GO:0003184), ventricular septum development (GO:0003281), regulation of transcription by RNA polymerase II (GO:0006357), immune response (GO:0006955), zygotic specification of dorsal/ventral axis (GO:0007352), negative regulation of cell population proliferation (GO:0008285), anatomical structure morphogenesis (GO:0009653), cell differentiation (GO:0030154), negative regulation of ossification (GO:0030279), BMP signaling pathway (GO:0030509), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), cell-substrate adhesion (GO:0031589), response to lipopolysaccharide (GO:0032496), negative regulation of activin receptor signaling pathway (GO:0032926), response to laminar fluid shear stress (GO:0034616), aorta development (GO:0035904), negative regulation of apoptotic process (GO:0043066), response to estrogen (GO:0043627), fat cell differentiation (GO:0045444), negative regulation of osteoblast differentiation (GO:0045668), negative regulation of SMAD protein signal transduction (GO:0060392), SMAD protein signal transduction (GO:0060395), coronary vasculature development (GO:0060976), positive regulation of miRNA transcription (GO:1902895), heart valve development (GO:0003170), regulation of DNA-templated transcription (GO:0006355), negative regulation of cell differentiation (GO:0045596), cellular response to growth factor stimulus (GO:0071363), transforming growth factor beta receptor superfamily signaling pathway (GO:0141091)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), chromatin binding (GO:0003682), ubiquitin protein ligase binding (GO:0031625), type I transforming growth factor beta receptor binding (GO:0034713), identical protein binding (GO:0042802), metal ion binding (GO:0046872), co-SMAD binding (GO:0070410), I-SMAD binding (GO:0070411), R-SMAD binding (GO:0070412), type I activin receptor binding (GO:0070698), protein sequestering activity (GO:0140311), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515), activin receptor binding (GO:0070697)

GO Cellular Component (12): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cilium (GO:0005929), nuclear body (GO:0016604), protein-containing complex (GO:0032991), ciliary basal body (GO:0036064), heteromeric SMAD protein complex (GO:0071144), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by TGFB family members	1
Transcriptional regulation by RUNX2	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	3
SMAD binding	3
heart valve morphogenesis	2
binding	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
mesonephric tubule development	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
aortic valve development	1
mitral valve development	1
atrioventricular valve morphogenesis	1
pulmonary valve development	1
cardiac ventricle development	1
cardiac septum development	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
immune system process	1
response to stimulus	1
embryonic axis specification	1
dorsal/ventral axis specification	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
developmental process	1
anatomical structure development	1
cellular developmental process	1
ossification	1
regulation of ossification	1
negative regulation of multicellular organismal process	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
cell adhesion	1

Protein interactions and networks

STRING

1892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD6	SMURF1	Q9HCE7	996
SMAD6	TGFBR1	P36897	958
SMAD6	SMAD4	Q13485	958
SMAD6	SMURF2	Q9HAU4	934
SMAD6	TGFB1	P01137	837
SMAD6	PELI1	Q96FA3	767
SMAD6	SKIL	P12756	735
SMAD6	BMP7	P18075	731
SMAD6	TGFB2	P08112	726
SMAD6	BMP2	P12643	715
SMAD6	SMAD7	O15105	701
SMAD6	BMP4	P12644	685
SMAD6	CHRD	Q9H2X0	661
SMAD6	TGFBR2	P37173	659
SMAD6	ACVR1	Q04771	644

IntAct

26 interactions, top by confidence:

A	B	Type	Score
PRKX	SMAD6	psi-mi:“MI:0915”(physical association)	0.630
SMAD6	PRKX	psi-mi:“MI:0915”(physical association)	0.630
PRKX	SMAD6	psi-mi:“MI:0217”(phosphorylation reaction)	0.630
SMAD6	SMAD1	psi-mi:“MI:0915”(physical association)	0.570
SMAD1	SMAD6	psi-mi:“MI:0914”(association)	0.570
SMAD6	SMAD6	psi-mi:“MI:0915”(physical association)	0.510
SMAD6		psi-mi:“MI:0915”(physical association)	0.400
ARK2C	SMAD6	psi-mi:“MI:0915”(physical association)	0.400
SMAD6	UBE2O	psi-mi:“MI:0915”(physical association)	0.400
RUNX2	SMAD6	psi-mi:“MI:0915”(physical association)	0.400
SMAD6	RUNX2	psi-mi:“MI:0915”(physical association)	0.400
SMAD6	Runx2	psi-mi:“MI:0915”(physical association)	0.400
SMAD6	CHRM5	psi-mi:“MI:0915”(physical association)	0.370
FKBP1A	SMAD6	psi-mi:“MI:0915”(physical association)	0.370
SMAD6	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
SMURF2	SMAD6	psi-mi:“MI:0915”(physical association)	0.370
SMAD6	RPS6KA5	psi-mi:“MI:0915”(physical association)	0.370
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
Smad6	DDX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (88): SMAD7 (Affinity Capture-Western), CTBP1 (Affinity Capture-Western), PIAS3 (Affinity Capture-Western), SMAD6 (Affinity Capture-Western), SMURF1 (Affinity Capture-Western), SMAD6 (Affinity Capture-Western), SMAD6 (Two-hybrid), SMAD6 (Affinity Capture-Western), SMURF1 (PCA), TNFAIP3 (Affinity Capture-Western), SMAD6 (Affinity Capture-Western), SMAD6 (Two-hybrid), SMAD6 (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), TAB1 (Affinity Capture-Western)

ESM2 similar proteins: A0A140LIA7, A0A1B0GTL2, A2VDX9, A3FFS8, A6NCS6, A8MVW0, K9M1U5, O43541, P01588, P03971, P03972, P07321, P07865, P0C7N4, P0DPE3, P13725, P27106, P29676, P33707, P33708, P33709, P48617, P49000, P49157, P53346, P79295, Q02011, Q0Z956, Q16619, Q1HCM0, Q28513, Q29RM6, Q5BLP8, Q5S1V9, Q60753, Q63086, Q65Z15, Q6H8S9, Q6H8T0, Q6H8T1

Diamond homologs: O15105, O35182, O35253, O43541, O88406, Q9W734, O15198, O54835, O70436, O70437, P84022, P84023, P84024, P84025, P97471, Q13485, Q15796, Q1HE26, Q1W668, Q21733, Q5R7C0, Q62432, Q8BUN5, Q9GKQ9, Q9I9P9, Q9JIW5, P42003, F5GUE5, P45896, P45897, P70340, P97454, P97588, Q02330, Q15797, Q1JQA2, Q56I99, Q5R6H7, Q95QI7, Q99717

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
SMAD6	down-regulates	SMAD1	binding
SMURF1	“down-regulates activity”	SMAD6	relocalization
SMAD6	down-regulates	NR2C2	binding
SMAD6	down-regulates	TAB1	binding
SMAD6	“down-regulates activity”	TGFBR1	binding
SMAD6	up-regulates	PELI1	binding
UBE2O	down-regulates	SMAD6	ubiquitination
SMAD6	“down-regulates activity”	SMAD4	binding
SMAD6	down-regulates	SMAD1/4	binding
SMURF	“down-regulates activity”	SMAD6	relocalization
SMAD6	“down-regulates quantity by destabilization”	TBX6	binding
SMAD6	“up-regulates activity”	SMURF1	binding
PRKX	“up-regulates activity”	SMAD6	phosphorylation
SMAD6	“down-regulates activity”	SMAD3	binding
SMAD6	“up-regulates activity”	HOXC8	binding
SMAD6	down-regulates	BMPR1A
SMAD1	“up-regulates quantity”	SMAD6	“transcriptional regulation”
SMAD5	“up-regulates quantity”	SMAD6	“transcriptional regulation”
SMAD6	“down-regulates activity”	MAP3K7	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1331 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	36
Uncertain significance	816
Likely benign	341
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174545	NM_005585.5(SMAD6):c.957_958insGCAA (p.Ser320fs)	Pathogenic
1174547	NM_005585.5(SMAD6):c.3dup (p.Phe2fs)	Pathogenic
1174549	NM_005585.5(SMAD6):c.1012G>T (p.Glu338Ter)	Pathogenic
1174551	NM_005585.5(SMAD6):c.872del (p.Leu291fs)	Pathogenic
1174552	NM_005585.5(SMAD6):c.859G>T (p.Glu287Ter)	Pathogenic
1174553	NM_005585.5(SMAD6):c.439_457dup (p.Ala153fs)	Pathogenic
1174556	NM_005585.5(SMAD6):c.1416G>A (p.Trp472Ter)	Pathogenic
1174562	NM_005585.5(SMAD6):c.1309A>T (p.Lys437Ter)	Pathogenic
1174563	NM_005585.5(SMAD6):c.24del (p.Leu9fs)	Pathogenic
1174568	NM_005585.5(SMAD6):c.283del (p.Glu95fs)	Pathogenic
1174569	NM_005585.5(SMAD6):c.294del (p.Gly99fs)	Pathogenic
1174570	NM_005585.5(SMAD6):c.325del (p.Glu109fs)	Pathogenic
1174571	NM_005585.5(SMAD6):c.67del (p.Glu23fs)	Pathogenic
1174574	NM_005585.5(SMAD6):c.511G>A (p.Glu171Lys)	Pathogenic
1174576	NM_005585.5(SMAD6):c.1227del (p.Ile410fs)	Pathogenic
1174578	NM_005585.5(SMAD6):c.1419del (p.Cys475fs)	Pathogenic
1174579	NM_005585.5(SMAD6):c.1285A>T (p.Lys429Ter)	Pathogenic
1174580	NM_005585.5(SMAD6):c.1010G>A (p.Trp337Ter)	Pathogenic
1174581	NM_005585.5(SMAD6):c.1132G>T (p.Glu378Ter)	Pathogenic
1174584	NM_005585.5(SMAD6):c.217G>T (p.Gly73Ter)	Pathogenic
1174585	NM_005585.5(SMAD6):c.1099dup (p.Cys367fs)	Pathogenic
1174586	NM_005585.5(SMAD6):c.165C>A (p.Cys55Ter)	Pathogenic
1174870	NM_005585.5(SMAD6):c.775del (p.Val259fs)	Pathogenic
1705020	NM_005585.5(SMAD6):c.584T>G (p.Val195Gly)	Pathogenic
2430871	NM_005585.5(SMAD6):c.817G>C (p.Glu273Gln)	Pathogenic
2662629	NM_005585.5(SMAD6):c.953-1G>A	Pathogenic
3390849	NM_005585.5(SMAD6):c.893del (p.Leu298fs)	Pathogenic
37111	NM_005585.5(SMAD6):c.1451G>T (p.Cys484Phe)	Pathogenic
3769868	NM_005585.5(SMAD6):c.641del (p.Arg214fs)	Pathogenic
4531510	NM_005585.5(SMAD6):c.344G>A (p.Trp115Ter)	Pathogenic

SpliceAI

1223 predictions. Top by Δscore:

Variant	Effect	Δscore
15:66711666:A:AG	acceptor_gain	1.0000
15:66711667:G:GG	acceptor_gain	1.0000
15:66711723:GG:G	donor_gain	1.0000
15:66711724:GG:G	donor_gain	1.0000
15:66711725:G:GG	donor_gain	1.0000
15:66711726:T:G	donor_loss	1.0000
15:66716415:CCACA:C	acceptor_loss	1.0000
15:66716416:CACA:C	acceptor_loss	1.0000
15:66716417:ACAG:A	acceptor_loss	1.0000
15:66716418:CAG:C	acceptor_loss	1.0000
15:66716419:A:AG	acceptor_gain	1.0000
15:66716419:A:T	acceptor_loss	1.0000
15:66716420:G:GG	acceptor_gain	1.0000
15:66716420:GAT:G	acceptor_gain	1.0000
15:66716420:GATC:G	acceptor_gain	1.0000
15:66716420:GATCT:G	acceptor_gain	1.0000
15:66716495:TCAG:T	donor_loss	1.0000
15:66716496:CAG:C	donor_loss	1.0000
15:66716497:AG:A	donor_loss	1.0000
15:66716498:GGTC:G	donor_loss	1.0000
15:66716500:T:A	donor_loss	1.0000
15:66780996:GAC:G	acceptor_gain	1.0000
15:66711662:TTCCA:T	acceptor_loss	0.9900
15:66711663:TCCAG:T	acceptor_loss	0.9900
15:66711664:CCAGA:C	acceptor_loss	0.9900
15:66711665:CA:C	acceptor_loss	0.9900
15:66711666:AG:A	acceptor_loss	0.9900
15:66711667:GA:G	acceptor_gain	0.9900
15:66711667:GAAT:G	acceptor_gain	0.9900
15:66711667:GAATC:G	acceptor_gain	0.9900

AlphaMissense

3144 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:66704036:T:C	C260R	1.000
15:66781035:T:A	W331R	1.000
15:66781035:T:C	W331R	1.000
15:66781037:G:C	W331C	1.000
15:66781037:G:T	W331C	1.000
15:66781040:C:G	C332W	1.000
15:66781050:T:C	Y336H	1.000
15:66781050:T:G	Y336D	1.000
15:66781053:T:A	W337R	1.000
15:66781053:T:C	W337R	1.000
15:66781054:G:C	W337S	1.000
15:66781055:G:C	W337C	1.000
15:66781055:G:T	W337C	1.000
15:66781068:C:A	R342S	1.000
15:66781074:G:C	G344R	1.000
15:66781075:G:A	G344D	1.000
15:66781075:G:T	G344V	1.000
15:66781113:T:C	F357L	1.000
15:66781115:C:A	F357L	1.000
15:66781115:C:G	F357L	1.000
15:66781212:G:C	G390R	1.000
15:66781213:G:A	G390D	1.000
15:66781213:G:T	G390V	1.000
15:66781245:T:A	W401R	1.000
15:66781245:T:C	W401R	1.000
15:66781275:T:A	F411I	1.000
15:66781275:T:C	F411L	1.000
15:66781275:T:G	F411V	1.000
15:66781276:T:C	F411S	1.000
15:66781276:T:G	F411C	1.000

dbSNP variants (sampled 300 via entrez): RS1000013143 (15:66772948 C>T), RS1000045247 (15:66734869 G>A), RS1000103933 (15:66728839 C>T), RS1000138063 (15:66735173 C>A), RS1000147516 (15:66703064 C>A,T), RS1000160179 (15:66758326 A>G,T), RS1000172185 (15:66775973 C>G,T), RS1000210592 (15:66704828 TC>T), RS1000217089 (15:66737834 C>T), RS1000264094 (15:66737553 G>A), RS1000286216 (15:66729027 G>A), RS1000304119 (15:66711170 A>G), RS1000314952 (15:66775713 G>A,T), RS1000344684 (15:66743157 C>G), RS1000364165 (15:66706957 A>G)

Disease associations

OMIM: gene MIM:602931 | disease phenotypes: MIM:614823, MIM:179300, MIM:603596, MIM:617439, MIM:613795, MIM:109730, MIM:610805, MIM:123100, MIM:612285, MIM:607086, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
SMAD6-related disease	Definitive	Autosomal dominant
radioulnar synostosis, nonsyndromic, susceptibility to	Strong	Autosomal dominant
craniosynostosis 7	Strong	Autosomal dominant
aortic valve disease 2	Moderate	Autosomal dominant
congenital radioulnar synostosis	Supportive	Unknown
familial bicuspid aortic valve	Supportive	Autosomal dominant
congenital heart defects, multiple types	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
SMAD6-related disease	Definitive	AD

Mondo (18): aortic valve disease 2 (MONDO:0013902), SMAD6-related disease (MONDO:0700324), congenital radioulnar synostosis (MONDO:0017985), radioulnar synostosis, nonsyndromic, susceptibility to (MONDO:0100183), polydactyly (MONDO:0021003), craniosynostosis 7 (MONDO:0044315), thoracic aortic aneurysm (MONDO:0005396), cardiogenetic disease (MONDO:0100547), aneurysm-osteoarthritis syndrome (MONDO:0013426), aortic valve disease 1 (MONDO:0024523), congenital heart disease (MONDO:0005453), congenital anomaly of kidney and urinary tract (MONDO:0019719), craniosynostosis (MONDO:0015469), Joubert syndrome 9 (MONDO:0012849), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625)

Orphanet (7): Isolated radio-ulnar synostosis (Orphanet:3269), Aneurysm-osteoarthritis syndrome (Orphanet:284984), Renal or urinary tract malformation (Orphanet:93545), Craniosynostosis (Orphanet:1531), Joubert syndrome with oculorenal defect (Orphanet:2318), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Esophageal atresia (Orphanet:1199)

HPO phenotypes

26 total (27 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000750	Delayed speech and language development
HP:0000822	Hypertension
HP:0001363	Craniosynostosis
HP:0001642	Pulmonic stenosis
HP:0001647	Bicuspid aortic valve
HP:0001650	Aortic valve stenosis
HP:0001653	Mitral regurgitation
HP:0001655	Patent foramen ovale
HP:0001659	Aortic regurgitation
HP:0001680	Coarctation of aorta
HP:0002974	Radioulnar synostosis
HP:0003577	Congenital onset
HP:0004380	Aortic valve calcification
HP:0004383	Hypoplastic left ventricle
HP:0004933	Ascending aortic dissection
HP:0004942	Aortic aneurysm
HP:0004962	Thoracic aorta calcification
HP:0004963	Calcification of the aorta
HP:0005113	Aortic arch aneurysm
HP:0006394	Limited pronation/supination of forearm
HP:0006687	Aortic tortuosity
HP:0011103	Abnormal left ventricular outflow tract morphology
HP:0012758	Neurodevelopmental delay
HP:0030148	Heart murmur
HP:4000158	Typified by high penetrance
HP:0010442	Polydactyly

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST001521_8	Subcutaneous adipose tissue	9.000000e-06
GCST002392_1	Lung cancer (smoking interaction)	4.000000e-06
GCST002782_225	Waist-to-hip ratio adjusted for body mass index	1.000000e-06
GCST002782_226	Waist-to-hip ratio adjusted for body mass index	1.000000e-10
GCST002782_227	Waist-to-hip ratio adjusted for body mass index	3.000000e-07
GCST002782_228	Waist-to-hip ratio adjusted for body mass index	9.000000e-06
GCST002782_229	Waist-to-hip ratio adjusted for body mass index	3.000000e-11
GCST004064_65	Waist-hip ratio	8.000000e-09
GCST004505_104	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	7.000000e-06
GCST005212_39	Asthma	7.000000e-15
GCST006862_17	Asthma	9.000000e-16
GCST006957_4	Severe aortic features in Marfan syndrome	8.000000e-06
GCST007581_14	Carpal tunnel syndrome	4.000000e-10
GCST007993_15	Asthma (adult onset)	6.000000e-12
GCST007995_45	Asthma (childhood onset)	3.000000e-26
GCST008839_515	Height	3.000000e-11
GCST009269_16	Dental caries (decayed and filled deciduous teeth)	2.000000e-06
GCST009798_50	Asthma	4.000000e-07
GCST009798_54	Asthma	6.000000e-09
GCST009798_80	Asthma	1.000000e-45
GCST010002_173	Refractive error	2.000000e-12
GCST010083_282	Hemoglobin levels	1.000000e-13
GCST012227_291	Hip circumference adjusted for BMI	3.000000e-13
GCST012227_292	Hip circumference adjusted for BMI	1.000000e-08
GCST012227_293	Hip circumference adjusted for BMI	4.000000e-10
GCST90000025_218	Appendicular lean mass	7.000000e-40
GCST90000025_219	Appendicular lean mass	6.000000e-11
GCST90002383_274	Hematocrit	6.000000e-12
GCST90002384_388	Hemoglobin	1.000000e-09
GCST90002390_419	Mean corpuscular hemoglobin	2.000000e-09

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0006527	smoking status measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004343	waist-hip ratio
EFO:0004318	smoking behavior
EFO:1002011	adult onset asthma
EFO:0004509	hemoglobin measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0004348	hematocrit
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D017545	Aortic Aneurysm, Thoracic	C14.907.055.239.125; C14.907.109.139.125
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D017689	Polydactyly	C05.660.585.600; C16.131.621.585.600
C566906	Cakut (supp.)
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)
C567364	Joubert Syndrome 9 (supp.)
C562408	Radioulnar Synostosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	7
Valproic Acid	decreases expression, increases expression, increases methylation	3
bisphenol A	affects expression, increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
geraniol	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
cupric chloride	decreases expression	1
galangin	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Calcitriol	decreases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1HN	Abcam A-549 SMAD6 KO	Cancer cell line	Male
CVCL_D8AT	Ubigene A-549 SMAD6 KO	Cancer cell line	Male
CVCL_D8VK	Ubigene HCT 116 SMAD6 KO	Cancer cell line	Male
CVCL_D9SA	Ubigene HEK293 SMAD6 KO	Transformed cell line	Female
CVCL_E0PC	Ubigene HeLa SMAD6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00339053	PHASE4	UNKNOWN	Immunonutrition and Thoracoabdominal Aorta Aneurysm Repair
NCT02291718	PHASE4	COMPLETED	Thoracoabdominal Arortic CTA Study
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
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