SMAD2

Summary

SMAD2 (SMAD family member 2, HGNC:6768) is a protein-coding gene on chromosome 18q21.1, encoding SMAD family member 2 (Q15796). Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.

The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene ‘mothers against decapentaplegic’ (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 4087 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 513 total — 23 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 148
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 112 downstream targets (CollecTRI)
• MANE Select transcript: NM_005901

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6768
Approved symbol	SMAD2
Name	SMAD family member 2
Location	18q21.1
Locus type	gene with protein product
Status	Approved
Aliases	MADR2, JV18-1
Ensembl gene	ENSG00000175387
Ensembl biotype	protein_coding
OMIM	601366
Entrez	4087

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 42 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000262160, ENST00000356825, ENST00000402690, ENST00000585978, ENST00000586040, ENST00000586487, ENST00000586514, ENST00000587269, ENST00000587353, ENST00000587421, ENST00000589877, ENST00000591214, ENST00000878358, ENST00000878359, ENST00000878360, ENST00000878361, ENST00000878362, ENST00000878363, ENST00000878364, ENST00000878365, ENST00000878366, ENST00000878367, ENST00000878368, ENST00000878369, ENST00000878370, ENST00000878371, ENST00000878372, ENST00000936519, ENST00000936520, ENST00000936521, ENST00000936522, ENST00000936523, ENST00000966643, ENST00000966644, ENST00000966645, ENST00000966646, ENST00000966647, ENST00000966648, ENST00000966649, ENST00000966650, ENST00000966651, ENST00000966652, ENST00000966653, ENST00000966654

RefSeq mRNA: 3 — MANE Select: NM_005901 NM_001003652, NM_001135937, NM_005901

CCDS: CCDS11934

Canonical transcript exons

ENST00000262160 — 11 exons

Exon	Start	End
ENSE00001191187	47896521	47896809
ENSE00001248481	47845663	47845800
ENSE00001248484	47848475	47848687
ENSE00001248493	47851274	47851327
ENSE00001248503	47868323	47868457
ENSE00001533831	47930361	47930659
ENSE00001598119	47845340	47845484
ENSE00001728507	47865059	47865133
ENSE00003564555	47869243	47869436
ENSE00003738839	47808957	47841950
ENSE00003789792	47870475	47870564

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.6214 / max 220.0089, expressed in 1818 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171845	14.2207	1790
171843	3.8222	1569
171844	3.1294	1465
171846	2.8082	1444
171842	2.7713	1398
171847	1.5851	1080
171849	0.7223	326
171848	0.3993	173
171841	0.1628	74

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.71	gold quality
sperm	CL:0000019	98.20	gold quality
male germ cell	CL:0000015	97.53	gold quality
adrenal tissue	UBERON:0018303	97.41	gold quality
tendon	UBERON:0000043	97.35	gold quality
secondary oocyte	CL:0000655	96.87	gold quality
germinal epithelium of ovary	UBERON:0001304	96.50	gold quality
monocyte	CL:0000576	96.49	gold quality
islet of Langerhans	UBERON:0000006	96.37	gold quality
mononuclear cell	CL:0000842	96.33	gold quality
leukocyte	CL:0000738	96.22	gold quality
amniotic fluid	UBERON:0000173	96.22	gold quality
tendon of biceps brachii	UBERON:0008188	95.88	gold quality
hair follicle	UBERON:0002073	95.83	gold quality
oocyte	CL:0000023	95.82	gold quality
colonic epithelium	UBERON:0000397	95.80	gold quality
endothelial cell	CL:0000115	95.61	gold quality
sural nerve	UBERON:0015488	95.34	gold quality
rectum	UBERON:0001052	95.23	gold quality
ganglionic eminence	UBERON:0004023	95.17	gold quality
palpebral conjunctiva	UBERON:0001812	95.10	gold quality
stromal cell of endometrium	CL:0002255	94.92	gold quality
eye	UBERON:0000970	94.86	gold quality
gall bladder	UBERON:0002110	94.73	gold quality
ventricular zone	UBERON:0003053	94.71	gold quality
smooth muscle tissue	UBERON:0001135	94.69	gold quality
parietal pleura	UBERON:0002400	94.46	gold quality
gingival epithelium	UBERON:0001949	94.34	gold quality
pleura	UBERON:0000977	94.18	gold quality
epithelium of nasopharynx	UBERON:0001951	94.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.99
E-GEOD-124858	no	1002.84
E-CURD-135	no	779.05

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

112 targets.

Target	Regulation
ABCG2	Activation
ACAN	Repression
ACTA2	Unknown
ACTG2	Unknown
ADAM2
AGTR1	Unknown
AHR	Unknown
ALPI	Activation
ALPP	Activation
ANKRD1	Activation
APP	Activation
ATF3	Activation
BAX	Repression
BCL2	Unknown
BGLAP	Repression
BIRC5	Unknown
CCN1	Activation
CCN2	Unknown
CCND1	Unknown
CCNG2
CDH1	Unknown
CDKN1A	Unknown
CDX2
COL1A2	Unknown
COL2A1	Unknown
COL3A1	Repression
COL7A1	Activation
CSN2	Unknown
CSRP2	Activation
CXCL1	Activation

JASPAR motifs

Motif	Name	Family
MA1964.1	SMAD2	SMAD factors
MA1964.2	SMAD2	SMAD factors

JASPAR matrix evidence (PMIDs): PMID:21828274

Upstream regulators (CollecTRI, top): CEBPB, GGCX, KLF10, MYC, PIN1, TGFB1, TP53, ZNF451

miRNA regulators (miRDB)

347 targeting SMAD2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
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-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548P	99.98	72.25	3784

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling (PMID:11779503)
• repression of transactivating activity by association with a novel splice variant of CCAAT-binding factor C subunit (PMID:12023901)
• c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity (PMID:12034730)
• activation by transforming growth factor beta in absence of receptor endocytosis (PMID:12034739)
• HTLV-1 tax represses Smad-mediated TGF-beta signaling. (PMID:12097320)
• activation of TGF-beta1/Smad2 signaling is associated with airway remodeling in asthma (PMID:12170265)
• Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. (PMID:12191474)
• overexpression of adenoviral Smad1 and Smad2 proteins without exogenously added ligands induced inhibin B production (PMID:12354674)
• Levels of phosphorylated Smad2/3 are sensors of the interplay between effects of retinoic acid and TGF-beta or vitamin D3 on monocytic and granulocytic differentiation of HL-60 cells. (PMID:12393416)
• Phenotypic and functional changes associated with TGF-beta1-induced fibroblast terminal differentiation are differentially regulated by Smad2, Smad3, and Smad4. (PMID:12531695)
• TGF-beta1 inhibited IFN-gamma and TNF-alpha-induced TARC production in HaCaT cells via Smad2/3. Modulation of TGF-beta/Smad signaling pathway may be beneficial for treatment of atopic dermatitis. (PMID:12615364)
• In SMAD4-negative cell lines, TGF-beta caused Smad2 to move to the nucleus in a Smad4-independent fashion. Nuclear translocation of Smad2 was not sufficient to activate reporters for TGF-beta-induced transcriptional responses. (PMID:12618756)
• Results suggest that the Smad 2 may be the downstream signal transducers of TGF-beta(1) in human dental pulp cells. (PMID:12760775)
• A deletion of ‘G’ in the L3 loop (crucial in Smad-receptor interaction) & an insertion of ‘A’ in codon 122 (loss of MH2 domain) in cervical tumor cells caused frame shift & pretermination in Smad2, highlighting its important role in these tumors. (PMID:12894231)
• a signal transduction cascade of the TGF-beta/Smad signaling pathway, which is activated in the GEC, appears to be involved in the development of focal segmental glomerulosclerosis (PMID:14531804)
• Smad2, Smad3 and Smad4 contribute to the regulation of TGF-beta responses to varying extents, and exhibit distinct roles in different cell types (PMID:14555988)
• Tuberin (TSC2) interact with smad2/smad3 during TGF-beta1 growth regulation. (PMID:15066998)
• The most transcriptionally active splice variants of Smad2 are made in macrophages (but not SMCs) of fibrofatty lesions and are upregulated after cell differentiation from monocytes. Cyclin inhibitors are induced by Smads. Fibrous plaque SMCs make Smad2. (PMID:15166010)
• Differential gene expression of Smad2, a tumor suppressor gene, plays a significant role in the proliferation of breast cancer (PMID:15218362)
• Regulated cytoplasmic and nuclear retention may play a role in determining the distribution of Smads between the cytoplasm and the nucleus in both uninduced cells and upon TGF-beta induction. (PMID:15280432)
• Smad2/3 is activated in undifferentiated human embryonic stem cells and required for the expression of genes controlling Nodal signaling (PMID:15308665)
• TGF-beta-stimulation of transcription of PAI-1 is inhibited by VEGF, and TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, is suppressed by VEGF (PMID:15494412)
• NEDD4-2 bound to TGF-beta-specific R-Smads, Smads 2 and 3, in a ligand-dependent manner, and induced degradation of Smad2, but not Smad3 (PMID:15496141)
• p38 MAP kinase and Rho/ROCK pathways together with Smad2 and Smad3 are necessary for TGF-beta-mediated growth inhibition (PMID:15520018)
• caspase-3 is crucial for the differentiation of bone marrow stromal stem cells by influencing TGF-beta/Smad2 pathway and cell cycle progression (PMID:15599395)
• internalization is important for transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells (PMID:15613484)
• c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence. (PMID:15665291)
• TGF-beta signaling suppresses nuclear export of Smad4 by chromosome region maintenance 1 and targets Smad4 into the nucleus; mutations in Smad4 that affect its interaction with Smad2 or Smad3 impair nuclear accumulation of Smad4 in response to TGF-beta (PMID:15799969)
• UV-induced down-regulation of TbetaRII and the concerted over-expression of Smad7 may trigger the inhibition of the TGF-beta-induced phosphorylation of Smad2. (PMID:15811425)
• Smad4, but not Smad2, mediates TGF-beta1-induced MMP-2 expression in invasive extravillous trophoblasts (PMID:16146757)
• Distinct roles for Smad2 and Smad3 in TGFbeta1-induced CTGF expression and markers of EMT in human PTECs are reported. (PMID:16253118)
• TGF-beta-dependent nuclear accumulation of Smad2 is caused exclusively by selective nuclear trapping of phosphorylated, complexed Smad2 (PMID:16260601)
• TGF-beta1 acts on adjacent stromal cells to turn on Smad2 signalling that could lead to stromal decidualization. (PMID:16403803)
• Babo/dSmad2 signaling prior to metamorphosis may be widely required to prepare neurons for the dynamic environment present during metamorphosis. (PMID:16437159)
• A novel missense mutation of SMAD2, located in exon 8 at codon 276 TCG (ser) –>TTG (leu), was identified in head and neck squamous cell carcinoma cell line SCC-15. (PMID:16478646)
• Activation of Smad3 but not Smad2 is a key mechanism by which Angioteinsin ii mediates artriosclerosis. (PMID:16556868)
• Our data indicate that TGF-beta1 induces endothelial barrier dysfunction involving Smad2-dependent p38 activation, resulting in RhoA activation by possible transcriptional regulation. (PMID:16645187)
• These results suggest that p38 affects the phosphorylation of Smad2 and Smad3 differentially during TGF-beta signaling in human dental pulp cells and ERK1/2 might be involved in the process. (PMID:16924420)
• identified the small C-terminal domain phosphatase 1 (SCP1) as a specific phosphatase for Smad2/3 dephosphorylation in the linker and N terminus (PMID:17035229)
• mRNA expressed in human granulosa-luteal cells at oocyte retrieval. (PMID:17053951)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Smad2	ENSMUSG00000024563
rattus_norvegicus	Smad2	ENSRNOG00000018140

Paralogs (7): SMAD7 (ENSG00000101665), SMAD5 (ENSG00000113658), SMAD9 (ENSG00000120693), SMAD6 (ENSG00000137834), SMAD4 (ENSG00000141646), SMAD3 (ENSG00000166949), SMAD1 (ENSG00000170365)

Protein

Protein identifiers

SMAD family member 2 — Q15796 (reviewed: Q15796)

Alternative names: JV18-1, Mad-related protein 2, Mothers against decapentaplegic homolog 2

All UniProt accessions (7): B7Z5N5, Q15796, K7EJX0, K7EL92, K7ERC7, K7ESI8, Q53XR6

UniProt curated annotations — full annotation on UniProt →

Function. Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. Promotes TGFB1-mediated transcription of odontoblastic differentiation genes in dental papilla cells. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. May act as a tumor suppressor in colorectal carcinoma.

Subunit / interactions. Monomer; in the absence of TGF-beta. Heterodimer; in the presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4. Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD. Interacts with TAZ/WWRT1. Interacts with FOXH1. Interacts with SNW1. Interacts with CREB-binding protein (CBP) and EP300. Interacts with SNON. Interacts with ALK4/ACVR1B. Interacts with SKOR1. Interacts with SKOR2. Interacts with PRDM16. Interacts (via MH2 domain) with LEMD3. Interacts with RBPMS. Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif). Interacts with ZFHX3. Interacts with ZNF451. Interacts with SMURF2 when phosphorylated on Ser-465/467. Interacts with PPM1A. Interacts with TGF-beta. Interacts with TGFBR1. Interacts with TGIF. Interacts with SMAD3 and TRIM33. Interacts with ZNF580. Interacts with NEDD4L in response to TGF-beta. Interacts with HGS. Interacts with AIP1. Interacts with WWP1. Interacts with PML. Interacts weakly with ZNF8. Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors. Interacts with YAP1 (when phosphorylated at ‘Ser-127’). Interacts when phosphorylated with IPO7; the interaction facilitates translocation of SMAD2 to the nucleus. Interacts with MTMR4; negatively regulates TGF-beta signaling through SMAD2 dephosphorylation and retention in endosomes.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta.

Post-translational modifications. Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF-beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1. In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are ‘in use’ are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover. Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta.

Disease relevance. Congenital heart defects, multiple types, 8, with or without heterotaxy (CHTD8) [MIM:619657] An autosomal dominant disorder characterized by congenital developmental abnormalities involving structures of the heart. Common CHTD8 features include double-outlet right ventricle, unbalanced complete atrioventricular canal, and valvular anomalies. Vascular anomalies include dextroposition of the great arteries, anomalous pulmonary venous return, and superior vena cava to left atrium defect. Patients may also exhibit laterality defects, including dextrocardia, atrial isomerism, dextrogastria, left-sided gallbladder, and intestinal malrotation. The disease is caused by variants affecting the gene represented in this entry. Loeys-Dietz syndrome 6 (LDS6) [MIM:619656] A form of Loeys-Dietz syndrome, a syndrome with widespread systemic involvement characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Most LDS6 patients have thoracic aortic aneurysm involving the ascending aorta and/or aortic root, but cerebral and iliac arteries can be affected, and abdominal aortic aneurysm has been observed. Arterial tortuosity involving cerebral vessels, the aorta, and/or iliac arteries has also been reported. LDS6 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the dwarfin/SMAD family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15796-1	Long	yes
Q15796-2	Short, Smad2Deltaexon3

RefSeq proteins (3): NP_001003652, NP_001129409, NP_005892* (*=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 (80 total): sequence variant 17, strand 15, modified residue 13, mutagenesis site 13, helix 8, binding site 4, domain 2, compositionally biased region 2, initiator methionine 1, chain 1, splice variant 1, region of interest 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
6YIA	X-RAY DIFFRACTION	1.3
6M64	X-RAY DIFFRACTION	1.45
1KHX	X-RAY DIFFRACTION	1.8
5XOD	X-RAY DIFFRACTION	1.85
6ZVQ	X-RAY DIFFRACTION	2.03
1DEV	X-RAY DIFFRACTION	2.2
1U7V	X-RAY DIFFRACTION	2.7
5ZOJ	X-RAY DIFFRACTION	2.79
7CO1	X-RAY DIFFRACTION	3.3
2LB3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15796-F1	78.50	0.56

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): 161; 166; 74; 149

Post-translational modifications (13): 2, 8, 19, 220, 240, 245, 250, 255, 458, 460, 464, 465, 467

Mutagenesis-validated functional residues (13):

Position	Phenotype
19	loss of acetylation.
20	no effect on acetylation.
221–225	loss of binding to smurf2.
368	loss of interaction with pmepa1.
381	loss of binding to sara.
398	increased binding to ppm1a.
464	loss of phosphorylation by tgfbr1; when associated with a-465 and a-467.
465–467	binds ranbp3.
465–467	greatly reduced ranbp2 binding.
465	no change in binding to ppm1a. loss of phosphorylation by tgfbr1; when associated with a-464 and a-467.
465	no change in binding to ppm1a.
467	no change in binding to ppm1a. loss of phosphorylation by tgfbr1; when associated with a-464 and a-465.
467	no change in binding to ppm1a.

Function

Pathways and Gene Ontology

Reactome pathways

36 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1502540	Signaling by Activin
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-3304356	SMAD2/3 Phosphorylation Motif Mutants in Cancer
R-HSA-3311021	SMAD4 MH2 Domain Mutants in Cancer
R-HSA-3315487	SMAD2/3 MH2 Domain Mutants in Cancer
R-HSA-3656532	TGFBR1 KD Mutants in Cancer
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9796292	Formation of axial mesoderm
R-HSA-9823730	Formation of definitive endoderm
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-3304347	Loss of Function of SMAD4 in Cancer
R-HSA-3304349	Loss of Function of SMAD2/3 in Cancer
R-HSA-3304351	Signaling by TGF-beta Receptor Complex in Cancer
R-HSA-3656534	Loss of Function of TGFBR1 in Cancer
R-HSA-392499	Metabolism of proteins
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5688426	Deubiquitination

MSigDB gene sets: 775 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GCACCTT_MIR18A_MIR18B, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOBP_AXIS_SPECIFICATION, GGTGTGT_MIR329, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_ENDOCARDIAL_CUSHION_DEVELOPMENT

GO Biological Process (61): ureteric bud development (GO:0001657), in utero embryonic development (GO:0001701), endoderm formation (GO:0001706), mesoderm formation (GO:0001707), determination of left/right asymmetry in lateral mesoderm (GO:0003140), aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), endocardial cushion morphogenesis (GO:0003203), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), transforming growth factor beta receptor signaling pathway (GO:0007179), zygotic specification of dorsal/ventral axis (GO:0007352), gastrulation (GO:0007369), cell population proliferation (GO:0008283), anatomical structure morphogenesis (GO:0009653), response to glucose (GO:0009749), post-embryonic development (GO:0009791), anterior/posterior pattern specification (GO:0009952), positive regulation of gene expression (GO:0010628), positive regulation of epithelial to mesenchymal transition (GO:0010718), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), insulin secretion (GO:0030073), cell differentiation (GO:0030154), negative regulation of ossification (GO:0030279), lung development (GO:0030324), positive regulation of BMP signaling pathway (GO:0030513), pancreas development (GO:0031016), primary miRNA processing (GO:0031053), activin receptor signaling pathway (GO:0032924), organ growth (GO:0035265), intracellular signal transduction (GO:0035556), nodal signaling pathway (GO:0038092), cell fate commitment (GO:0045165), negative regulation of cell differentiation (GO:0045596), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), paraxial mesoderm morphogenesis (GO:0048340), embryonic foregut morphogenesis (GO:0048617), embryonic cranial skeleton morphogenesis (GO:0048701)

GO Molecular Function (23): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), double-stranded DNA binding (GO:0003690), DNA-binding transcription factor activity (GO:0003700), transforming growth factor beta receptor binding (GO:0005160), phosphatase binding (GO:0019902), ubiquitin protein ligase binding (GO:0031625), type I transforming growth factor beta receptor binding (GO:0034713), identical protein binding (GO:0042802), SMAD binding (GO:0046332), metal ion binding (GO:0046872), tau protein binding (GO:0048156), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), co-SMAD binding (GO:0070410), I-SMAD binding (GO:0070411), R-SMAD binding (GO:0070412), disordered domain specific binding (GO:0097718), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (13): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), activin responsive factor complex (GO:0032444), protein-containing complex (GO:0032991), ciliary transition zone (GO:0035869), SMAD protein complex (GO:0071141), homomeric SMAD protein complex (GO:0071142), heteromeric SMAD protein complex (GO:0071144), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Gastrulation	3
Developmental Biology	2
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
Loss of Function of SMAD2/3 in Cancer	2
FOXO-mediated transcription	2
Signaling by TGFB family members	1
TGF-beta receptor signaling activates SMADs	1
Signaling by TGF-beta Receptor Complex	1
Loss of Function of SMAD4 in Cancer	1
Loss of Function of TGFBR1 in Cancer	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
SMAD binding	3
formation of primary germ layer	2
heart valve morphogenesis	2
gene expression	2
regulation of gene expression	2
transcription cis-regulatory region binding	2
protein binding	2
protein-containing complex	2
cytoplasm	2
RNA polymerase II transcription regulator complex	2
SMAD protein complex	2
mesonephric tubule development	1
chordate embryonic development	1
endoderm development	1
mesoderm morphogenesis	1
determination of left/right symmetry	1
lateral mesoderm development	1
aortic valve development	1
pulmonary valve development	1
heart morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
RNA biosynthetic process	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
embryonic axis specification	1
dorsal/ventral axis specification	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
cellular process	1
developmental process	1
anatomical structure development	1
response to hexose	1
multicellular organism development	1

Protein interactions and networks

STRING

4767 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD2	TGFBR1	P36897	998
SMAD2	FOXH1	O75593	997
SMAD2	ZFYVE9	O95405	996
SMAD2	SKIL	P12756	996
SMAD2	SMURF2	Q9HAU4	993
SMAD2	TRIM33	Q9UPN9	993
SMAD2	CTNNB1	P35222	991
SMAD2	SMAD4	Q13485	990
SMAD2	SMAD3	P84022	982
SMAD2	WTAP	Q15007	982
SMAD2	TGFBR2	P37173	979
SMAD2	DROSHA	Q9NRR4	978
SMAD2	METTL14	Q9HCE5	975
SMAD2	METTL3	Q86U44	969
SMAD2	TP53	P04637	967

IntAct

325 interactions, top by confidence:

A	B	Type	Score
SMAD4	SMAD2	psi-mi:“MI:0407”(direct interaction)	0.970
SMAD4	SMAD2	psi-mi:“MI:0915”(physical association)	0.970
SMAD2	SMAD4	psi-mi:“MI:0915”(physical association)	0.970
SMAD2	SMAD4	psi-mi:“MI:0914”(association)	0.970
SMAD4	SMAD2	psi-mi:“MI:2364”(proximity)	0.970
SKI	SMAD4	psi-mi:“MI:0914”(association)	0.940
SMAD4	SKI	psi-mi:“MI:0914”(association)	0.940
SKI	SMAD2	psi-mi:“MI:0915”(physical association)	0.870
SKI	SMAD3	psi-mi:“MI:0914”(association)	0.840
ZFYVE9	SMAD2	psi-mi:“MI:0407”(direct interaction)	0.830
ZFYVE9	SMAD2	psi-mi:“MI:0915”(physical association)	0.830
ZFYVE9	SMAD2	psi-mi:“MI:0403”(colocalization)	0.830
SMURF2	SMAD2	psi-mi:“MI:0407”(direct interaction)	0.810
SMAD4	FOXO3	psi-mi:“MI:0914”(association)	0.800

BioGRID (659): SMAD2 (Affinity Capture-Western), SMAD2 (Reconstituted Complex), SMAD2 (Affinity Capture-Western), FOXH1 (Affinity Capture-Western), CREBBP (Affinity Capture-Western), LEF1 (Affinity Capture-Western), NEDD4L (Reconstituted Complex), SMAD2 (Affinity Capture-Western), Dok1 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SMAD2 (Affinity Capture-Western), Rasd2 (Affinity Capture-Luminescence), Rab34 (Affinity Capture-Luminescence), Rhebl1 (Affinity Capture-Luminescence), Rab38 (Affinity Capture-Luminescence)

ESM2 similar proteins: A0A5N6H279, A6NDR6, A7J1T0, A7J1T2, B3P851, B4IC49, B4PRU6, C5DH39, C5DZR8, F4J6F6, M0R5D6, O43283, O54835, O70436, O88738, P05549, P06434, P06435, P16794, P42003, P46934, P97368, Q05323, Q0P4S0, Q11107, Q15796, Q1HKZ5, Q1W668, Q21733, Q27571, Q387Y5, Q567C6, Q56I99, Q56XX3, Q5R7C0, Q5R8X7, Q5YDB6, Q62432, Q6DIB4, Q77DJ5

Diamond homologs: O15198, O35182, O54835, O70436, O70437, P42003, P45896, P45897, P70340, P84022, P84023, P84024, P84025, P97454, P97471, P97588, Q02330, Q13485, Q15796, Q15797, Q1HE26, Q1JQA2, Q1W668, Q21733, Q56I99, Q5R6H7, Q5R7C0, Q62432, Q8BUN5, Q95QI7, Q99717, Q9GKQ9, Q9I8V2, Q9I962, Q9I9P9, Q9JIW5, Q9R1V3, Q9W7E7, O15105, O35253

SIGNOR signaling

112 interactions.

A	Effect	B	Mechanism
FOXH1	“up-regulates activity”	SMAD2	binding
SMAD2	“form complex”	SMAD2/SMURF2	binding
SMAD2	“up-regulates activity”	SMURF2	binding
MYC	down-regulates	SMAD2
KAT2A	up-regulates	SMAD2	binding
ITCH	up-regulates	SMAD2	ubiquitination
PML	up-regulates	SMAD2	binding
PML	“up-regulates activity”	SMAD2	binding
UCHL5	up-regulates	SMAD2	deubiquitination
PPM1A	down-regulates	SMAD2	dephosphorylation
KAT2B	up-regulates	SMAD2	acetylation
TUBB	down-regulates	SMAD2	binding
NEDD4L	down-regulates	SMAD2	ubiquitination
MTMR4	down-regulates	SMAD2	dephosphorylation
ZFYVE9	“up-regulates activity”	SMAD2	relocalization
MAPK11	down-regulates	SMAD2	phosphorylation
WWTR1	up-regulates	SMAD2	binding
WWTR1	“up-regulates activity”	SMAD2	binding
BMP2	up-regulates	SMAD2
MAPK3	up-regulates	SMAD2	phosphorylation
P300/PCAF	up-regulates	SMAD2	binding
P300/PCAF	“up-regulates activity”	SMAD2	acetylation
UCHL5	“up-regulates activity”	SMAD2	deubiquitination
MAPK3	“up-regulates activity”	SMAD2	phosphorylation
NEDD4L	“down-regulates activity”	SMAD2	ubiquitination
RANBP3	“down-regulates activity”	SMAD2	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 140 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by NODAL	5	24.8×	1e-03
Downregulation of SMAD2/3:SMAD4 transcriptional activity	5	18.4×	1e-03
Hedgehog ‘off’ state	6	10.7×	3e-03
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	6	8.8×	5e-03
Signaling by TGFB family members	6	6.9×	8e-03
Infectious disease	13	3.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
SMAD protein signal transduction	5	28.6×	2e-04
positive regulation of protein import into nucleus	5	16.5×	3e-03
positive regulation of miRNA transcription	7	15.9×	9e-05
transforming growth factor beta receptor signaling pathway	10	12.4×	1e-05
cellular response to UV	5	11.6×	7e-03
negative regulation of cell differentiation	5	11.2×	8e-03
positive regulation of protein localization to plasma membrane	5	10.6×	9e-03
negative regulation of cell growth	7	7.9×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — COAD, COADREAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	12
Uncertain significance	204
Likely benign	208
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1187876	NM_005901.6(SMAD2):c.544C>T (p.Arg182Ter)	Pathogenic
1201774	NM_005901.6(SMAD2):c.189del (p.Ala64fs)	Pathogenic
1327531	NM_005901.6(SMAD2):c.1369G>A (p.Gly457Arg)	Pathogenic
1327536	NM_005901.6(SMAD2):c.237-12A>G	Pathogenic
135628	NM_005901.6(SMAD2):c.822G>C (p.Trp274Cys)	Pathogenic
1385209	NM_005901.6(SMAD2):c.985A>G (p.Arg329Gly)	Pathogenic
1678810	NM_005901.6(SMAD2):c.1217A>G (p.Tyr406Cys)	Pathogenic
1805110	NM_005901.6(SMAD2):c.748_754del (p.Ser250fs)	Pathogenic
208683	NM_005901.6(SMAD2):c.935G>C (p.Cys312Ser)	Pathogenic
2584413	NM_005901.6(SMAD2):c.997+1G>T	Pathogenic
2743215	NM_005901.6(SMAD2):c.392T>A (p.Leu131Ter)	Pathogenic
2838928	NM_005901.6(SMAD2):c.1325T>G (p.Leu442Arg)	Pathogenic
2846439	NM_005901.6(SMAD2):c.961C>T (p.Arg321Ter)	Pathogenic
3237537	NM_005901.6(SMAD2):c.544dup (p.Arg182fs)	Pathogenic
3725012	NM_005901.6(SMAD2):c.1186C>T (p.Gln396Ter)	Pathogenic
4082329	NM_005901.6(SMAD2):c.880C>T (p.Gln294Ter)	Pathogenic
419441	NM_005901.6(SMAD2):c.475G>T (p.Glu159Ter)	Pathogenic
430050	NM_005901.6(SMAD2):c.173T>A (p.Leu58Ter)	Pathogenic
4725834	NM_005901.6(SMAD2):c.891_894del (p.Leu297_Thr298insTer)	Pathogenic
4727394	NM_005901.6(SMAD2):c.141_144dup (p.Val49fs)	Pathogenic
522075	NM_005901.6(SMAD2):c.773dup (p.Asn258fs)	Pathogenic
56824	NM_005901.6(SMAD2):c.784+1G>A	Pathogenic
818019	NM_005901.6(SMAD2):c.549_550insCC (p.Thr184fs)	Pathogenic
1685446	NM_005901.6(SMAD2):c.908C>G (p.Thr303Arg)	Likely pathogenic
1709170	NM_005901.6(SMAD2):c.507_508del (p.Arg169fs)	Likely pathogenic
1722766	NM_005901.6(SMAD2):c.1059T>G (p.Ser353Arg)	Likely pathogenic
2696102	NM_005901.6(SMAD2):c.655+1G>C	Likely pathogenic
2865243	NM_005901.6(SMAD2):c.394T>A (p.Trp132Arg)	Likely pathogenic
3341131	NM_005901.6(SMAD2):c.1045T>C (p.Cys349Arg)	Likely pathogenic
3384910	NM_005901.6(SMAD2):c.237-2A>G	Likely pathogenic

SpliceAI

2752 predictions. Top by Δscore:

Variant	Effect	Δscore
18:47845373:A:AC	donor_gain	1.0000
18:47845398:G:C	donor_gain	1.0000
18:47845412:TCAAA:T	donor_gain	1.0000
18:47845481:CAGC:C	acceptor_gain	1.0000
18:47845657:CCATA:C	donor_loss	1.0000
18:47845658:CATA:C	donor_loss	1.0000
18:47845659:ATACC:A	donor_loss	1.0000
18:47845660:TAC:T	donor_loss	1.0000
18:47845661:A:T	donor_loss	1.0000
18:47845662:CCTGG:C	donor_loss	1.0000
18:47848477:ATATG:A	donor_gain	1.0000
18:47865054:TTTA:T	donor_loss	1.0000
18:47865055:TTA:T	donor_loss	1.0000
18:47865056:TA:T	donor_loss	1.0000
18:47865058:C:CA	donor_loss	1.0000
18:47865129:CGTTT:C	acceptor_gain	1.0000
18:47865130:GTTTC:G	acceptor_loss	1.0000
18:47865131:TTT:T	acceptor_gain	1.0000
18:47865132:TT:T	acceptor_gain	1.0000
18:47865132:TTC:T	acceptor_loss	1.0000
18:47865133:TCTAC:T	acceptor_loss	1.0000
18:47865134:C:CA	acceptor_loss	1.0000
18:47865134:C:CC	acceptor_gain	1.0000
18:47865135:T:G	acceptor_loss	1.0000
18:47868050:A:AC	donor_gain	1.0000
18:47868051:C:CC	donor_gain	1.0000
18:47868336:A:AC	donor_gain	1.0000
18:47868337:C:CC	donor_gain	1.0000
18:47868337:CT:C	donor_gain	1.0000
18:47868348:AATT:A	donor_gain	1.0000

AlphaMissense

3035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:47841864:A:G	M456T	1.000
18:47841867:T:G	Q455P	1.000
18:47841873:A:G	L453S	1.000
18:47841876:A:T	V452E	1.000
18:47841877:C:A	V452L	1.000
18:47841877:C:G	V452L	1.000
18:47841882:T:A	D450V	1.000
18:47841882:T:G	D450A	1.000
18:47841883:C:A	D450Y	1.000
18:47841883:C:G	D450H	1.000
18:47841884:C:A	L449F	1.000
18:47841884:C:G	L449F	1.000
18:47841885:A:C	L449W	1.000
18:47841885:A:G	L449S	1.000
18:47841887:C:A	W448C	1.000
18:47841887:C:G	W448C	1.000
18:47841888:C:G	W448S	1.000
18:47841889:A:G	W448R	1.000
18:47841889:A:T	W448R	1.000
18:47841891:T:G	Q447P	1.000
18:47841894:A:G	L446P	1.000
18:47841897:G:C	P445R	1.000
18:47841897:G:T	P445H	1.000
18:47841900:C:A	G444V	1.000
18:47841900:C:T	G444E	1.000
18:47841901:C:G	G444R	1.000
18:47841901:C:T	G444R	1.000
18:47841906:A:G	L442P	1.000
18:47841906:A:T	L442Q	1.000
18:47841912:A:G	L440P	1.000

dbSNP variants (sampled 300 via entrez): RS1000019346 (18:47883515 T>C), RS1000019520 (18:47818297 C>A), RS1000060907 (18:47879988 G>A), RS1000068382 (18:47877837 T>C), RS1000111672 (18:47819136 T>A), RS1000112572 (18:47828596 C>A,T), RS1000116526 (18:47819487 T>C), RS1000196160 (18:47916034 T>G), RS1000198494 (18:47918854 G>A,C), RS1000209413 (18:47841533 C>A,T), RS1000252484 (18:47919030 C>T), RS1000276882 (18:47923630 T>C), RS1000286502 (18:47847003 A>C,T), RS1000287108 (18:47867500 T>G), RS1000367685 (18:47824705 T>C,G)

Disease associations

OMIM: gene MIM:601366 | disease phenotypes: MIM:607086, MIM:619656, MIM:619657, MIM:609192

GenCC curated gene-disease

Disease	Classification	Inheritance
Loeys-Dietz syndrome 6	Strong	Autosomal dominant
congenital heart defects, multiple types, 8, with or without heterotaxy	Strong	Autosomal dominant
Loeys-Dietz syndrome	Strong	Autosomal dominant
congenital heart disease	Moderate	Autosomal dominant
familial thoracic aortic aneurysm and aortic dissection	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
congenital heart disease	Definitive	AD
Loeys-Dietz syndrome 6	Definitive	AD

Mondo (6): familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), Loeys-Dietz syndrome 6 (MONDO:0030500), congenital heart defects, multiple types, 8, with or without heterotaxy (MONDO:0859213), Loeys-Dietz syndrome 1 (MONDO:0012212), Loeys-Dietz syndrome (MONDO:0018954), congenital heart disease (MONDO:0005453)

Orphanet (3): Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Loeys-Dietz syndrome (Orphanet:60030), Furlong syndrome (Orphanet:97295)

HPO phenotypes

148 total (30 of 148 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000494	Downslanted palpebral fissures
HP:0000525	Abnormality iris morphology
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000678	Dental crowding
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000776	Congenital diaphragmatic hernia
HP:0000822	Hypertension
HP:0000954	Single transverse palmar crease
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003993_32	Menarche (age at onset)	1.000000e-11
GCST004749_49	Lung cancer in ever smokers	8.000000e-06
GCST006281_14	Coronary artery disease in type 1 diabetes	2.000000e-06
GCST011494_81	Daytime nap	2.000000e-44

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007828	daytime rest measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D055947	Loeys-Dietz Syndrome	C05.660.207.532; C14.907.055.239.587; C14.907.109.139.587; C16.131.077.537; C16.320.510

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2396512 (SINGLE PROTEIN), CHEMBL3885604 (PROTEIN FAMILY)

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

ChEMBL bioactivities

16 potent at pChembl≥5 of 16 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.06	IC50	8.7	nM	CHEMBL2207988
7.52	IC50	30	nM	CHEMBL5271361
7.48	Kd	32.95	nM	CHEMBL5653589
7.48	ED50	32.95	nM	CHEMBL5653589
7.17	IC50	68	nM	CHEMBL5410106
7.17	IC50	68	nM	CHEMBL5439266
7.05	IC50	90	nM	CHEMBL5280678
7.00	IC50	100	nM	CHEMBL5405214
6.86	IC50	137	nM	CHEMBL3400936
6.85	IC50	140	nM	CHEMBL3400936
6.85	IC50	140	nM	CHEMBL5434170
6.63	IC50	236	nM	CHEMBL5267203
6.62	IC50	240	nM	CHEMBL5267203
6.62	IC50	240	nM	CHEMBL5403707

PubChem BioAssay actives

14 with measured affinity, of 28 total; 10 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(9E)-16-chloro-13,15-dihydroxy-5,6,6,10-tetramethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.0300	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149437: Binding affinity to human SMAD2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0330	uM
(5R,6S,7S,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.0680	uM
(5R,6S,7S,9Z)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.0680	uM
(5R,6S,9E)-16-chloro-13,15-dihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.0900	uM
(5R,6S,7R,9Z)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.1000	uM
(9E)-16-chloro-6,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.1370	uM
(5S,6S,7S,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.1400	uM
(5R,6S,7R,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1954729: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs by Promega reporter rene assay	ic50	0.2360	uM
(5S,6S,7R,9E)-16-chloro-7,13,15-trihydroxy-5,6,10-trimethyl-4-oxabicyclo[10.4.0]hexadeca-1(12),9,13,15-tetraene-3,11-dione	1985588: Inhibition of TGF-beta induced Smad2/3 signaling in human HepG2 cells harboring pRL-EF1alpha, (CAGA)9x-MLP-Luc plasmid assessed as luciferase activity incubated for 24 hrs	ic50	0.2400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases chemical synthesis, increases expression, increases reaction, decreases expression, affects phosphorylation (+6 more)	8
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	6
Cadmium Chloride	affects binding, increases abundance, increases expression, affects reaction, increases localization (+4 more)	5
bisphenol A	decreases reaction, increases expression, increases methylation, increases phosphorylation	4
trichostatin A	decreases reaction, increases expression, affects cotreatment, decreases expression	4
LY2109761	decreases reaction, increases expression, increases phosphorylation, decreases expression	4
Arsenic Trioxide	increases expression, affects reaction, decreases reaction, increases phosphorylation, decreases expression	4
Endosulfan	decreases expression, decreases phosphorylation, increases expression, increases phosphorylation, decreases reaction	4
Tretinoin	increases phosphorylation, increases reaction, decreases reaction, increases localization, decreases expression (+1 more)	4
sodium arsenite	increases expression, decreases expression, increases abundance, affects cotreatment, decreases reaction	3
4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide	decreases reaction, increases expression, decreases expression	3
Acetylcysteine	affects cotreatment, decreases reaction, increases expression, increases phosphorylation, decreases phosphorylation	3
Hydrogen Peroxide	affects cotreatment, increases expression, decreases expression, increases phosphorylation	3
Asbestos, Serpentine	affects localization, decreases response to substance, increases expression, increases phosphorylation	3
FR900359	decreases reaction, increases phosphorylation	2
cobaltous chloride	decreases expression	2
ochratoxin A	increases phosphorylation, affects reaction, increases response to substance, decreases reaction, increases expression	2
tamibarotene	decreases expression, increases phosphorylation	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects binding, decreases reaction, increases reaction, increases phosphorylation	2
entinostat	decreases expression, affects cotreatment	2
HTS 466284	decreases reaction, increases phosphorylation	2
Resveratrol	decreases expression	2
Vorinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance, decreases reaction	2
Cadmium	decreases reaction, increases abundance, increases phosphorylation, affects reaction	2
Doxorubicin	affects cotreatment, decreases reaction, increases phosphorylation, increases expression, decreases expression	2
Glucose	affects localization, increases phosphorylation, decreases reaction	2
Paraquat	increases reaction, increases expression, increases phosphorylation, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2

ChEMBL screening assays

20 unique, capped per target: 20 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2401267	Binding	Inhibition of TGF-beta-induced Smad2 phosphorylation in human MDA-MB-231 cells treated 12 hrs before TGF-beta challenge measured after 1 hr by Western blotting	Curcuminoids block TGF-β signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis. — J Nat Prod

Cellosaurus cell lines

42 cell lines: 39 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0399	LoVo	Cancer cell line	Male
CVCL_1266	HCC2998	Cancer cell line	Sex unspecified
CVCL_1625	OPM-2	Cancer cell line	Female
CVCL_2478	HCT 8	Cancer cell line	Male
CVCL_3770	OVK18	Cancer cell line	Female
CVCL_4V50	LoVo/irinotecan	Cancer cell line	Male
CVCL_4V72	OPM-2/BTZ	Cancer cell line	Female
CVCL_4V75	LoVo/L-OHP	Cancer cell line	Male
CVCL_4Y03	LoVo-Luc#2	Cancer cell line	Male
CVCL_5210	OPM-1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE