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Aliases for SMAD6 Gene

Aliases for SMAD6 Gene

  • SMAD Family Member 6 2 3 4 5
  • MAD Homolog 6 3 4
  • MADH6 3 4
  • MAD, Mothers Against Decapentaplegic Homolog 6 (Drosophila) 2
  • Mothers Against Decapentaplegic, Drosophila, Homolog Of, 6 3
  • SMAD, Mothers Against DPP Homolog 6 (Drosophila) 2
  • Mothers Against Decapentaplegic Homolog 6 3
  • SMAD, Mothers Against DPP Homolog 6 3
  • Mothers Against DPP Homolog 6 4
  • HsT17432 3
  • SMAD 6 4
  • HSMAD6 4
  • AOVD2 3
  • MADH7 3
  • Smad6 4

External Ids for SMAD6 Gene

Previous HGNC Symbols for SMAD6 Gene

  • MADH7
  • MADH6

Previous GeneCards Identifiers for SMAD6 Gene

  • GC15P064681
  • GC15P064781
  • GC15P066994
  • GC15P043830

Summaries for SMAD6 Gene

Entrez Gene Summary for SMAD6 Gene

  • 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.[provided by RefSeq, Sep 2014]

GeneCards Summary for SMAD6 Gene

SMAD6 (SMAD Family Member 6) is a Protein Coding gene. Diseases associated with SMAD6 include Aortic Valve Disease 2 and Familial Bicuspid Aortic Valve. Among its related pathways are Mesodermal Commitment Pathway and TGF-beta signaling pathway (KEGG). GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and chromatin binding. An important paralog of this gene is SMAD7.

UniProtKB/Swiss-Prot for SMAD6 Gene

  • Acts as a mediator of TGF-beta and BMP antiflammatory activity. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of proinflammatory genes. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions.

Gene Wiki entry for SMAD6 Gene

No data available for CIViC summary , Tocris Summary , PharmGKB "VIP" Summary , fRNAdb sequence ontologies and piRNA Summary for SMAD6 Gene

Genomics for SMAD6 Gene

Regulatory Elements for SMAD6 Gene

Enhancers for SMAD6 Gene
GeneHancer Identifier Enhancer Score Enhancer Sources Gene-Enhancer Score TSS distance (kb) Number of Genes Away Size (kb) Transcription Factor Binding Sites within enhancer Gene Targets for Enhancer
GH15G066678 1.8 FANTOM5 Ensembl ENCODE dbSUPER 12.7 -22.3 -22283 3.0 PKNOX1 FOXA2 CREB3L1 ARNT ZFP64 ARID4B DMAP1 SLC30A9 ZNF766 ZNF263 SMAD6 GC15P068446 LINC01169
GH15G066758 1.6 Ensembl ENCODE dbSUPER 12.3 +61.1 61130 8.8 PKNOX1 FOXA2 ZFP64 SIN3A FEZF1 YY1 FOS DEK ZNF263 SP5 ENSG00000260773 SMAD6 GC15M066763 ENSG00000274995
GH15G066743 1.6 Ensembl ENCODE dbSUPER 12.1 +46.3 46308 8.9 PKNOX1 ARID4B SIN3A FEZF1 ZNF2 ZNF207 FOS DEK ZNF263 ZHX2 ENSG00000260773 TIPIN SMAD6 ENSG00000274995 GC15M066763
GH15G066755 1.3 ENCODE dbSUPER 12.4 +54.9 54941 2.7 HNRNPUL1 PKNOX1 FOXA2 MLX ARID4B SIN3A FEZF1 YY1 ZNF766 ZNF416 SMAD6 ENSG00000260773 SNORD16 GC15M066763 ENSG00000274995
GH15G066728 1.3 Ensembl ENCODE dbSUPER 12.3 +28.0 28012 2.8 BCOR PKNOX1 ESRRA NFIB ZNF140 ZMYM3 SIN3A CEBPG RAD21 ZBTB7B SMAD6 RPL4 ZWILCH SNORD18A SNORD16 ENSG00000274995 PIR60751
- Elite enhancer and/or Elite enhancer-gene association Download GeneHancer data dump

Enhancers around SMAD6 on UCSC Golden Path with GeneCards custom track

Promoters for SMAD6 Gene
Ensembl Regulatory Elements (ENSRs) TSS Distance (bp) Size (bp) Binding Sites for Transcription Factors within promoters
ENSR00000078215 600 4201 PKNOX1 AGO1 ARID4B SIN3A FEZF1 ZNF2 ZBTB7B YY1 ZNF766 ZNF143

Transcription factor binding sites by QIAGEN in the SMAD6 gene promoter:

Genomic Location for SMAD6 Gene

66,702,100 bp from pter
66,782,848 bp from pter
80,749 bases
Plus strand

Genomic View for SMAD6 Gene

Genes around SMAD6 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
SMAD6 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for SMAD6 Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for SMAD6 Gene

Proteins for SMAD6 Gene

  • Protein details for SMAD6 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Recommended name:
    Mothers against decapentaplegic homolog 6
    Protein Accession:
    Secondary Accessions:
    • A9J6M5
    • O43654
    • Q15799
    • Q7Z7L4
    • Q96E31
    • Q9UKZ3

    Protein attributes for SMAD6 Gene

    496 amino acids
    Molecular mass:
    53497 Da
    Quaternary structure:
    • Interacts with NEDD4L (By similarity). Interacts with WWP1 (By similarity). 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.

    Alternative splice isoforms for SMAD6 Gene


neXtProt entry for SMAD6 Gene

Post-translational modifications for SMAD6 Gene

  • 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.
  • 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 (PubMed:23455153). Ubiquitinated by WWP1 (By similarity). Ubiquitinated by RNF165, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling (By similarity).
  • Phosphorylated by BMP type 1 receptor kinase and by PRKX.
  • Ubiquitination at isoforms=4173
  • Modification sites at PhosphoSitePlus

Other Protein References for SMAD6 Gene

No data available for DME Specific Peptides for SMAD6 Gene

Domains & Families for SMAD6 Gene

Gene Families for SMAD6 Gene

Suggested Antigen Peptide Sequences for SMAD6 Gene

GenScript: Design optimal peptide antigens:

Graphical View of Domain Structure for InterPro Entry



  • Belongs to the dwarfin/SMAD family.
  • Belongs to the dwarfin/SMAD family.
genes like me logo Genes that share domains with SMAD6: view

Function for SMAD6 Gene

Molecular function for SMAD6 Gene

UniProtKB/Swiss-Prot Function:
Acts as a mediator of TGF-beta and BMP antiflammatory activity. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of proinflammatory genes. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions.

Gene Ontology (GO) - Molecular Function for SMAD6 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding IDA 16491121
GO:0003677 DNA binding IEA --
GO:0003682 chromatin binding IDA 16491121
GO:0003700 transcription factor activity, sequence-specific DNA binding IEA --
GO:0005515 protein binding IPI 9436979
genes like me logo Genes that share ontologies with SMAD6: view
genes like me logo Genes that share phenotypes with SMAD6: view

Human Phenotype Ontology for SMAD6 Gene

HPO Id HPO Name Alternative Ids Definition Synonyms

Animal Models for SMAD6 Gene

MGI Knock Outs for SMAD6:

Animal Model Products

Inhibitory RNA Products

Flow Cytometry Products

No data available for Enzyme Numbers (IUBMB) , Transcription Factor Targets and HOMER Transcription for SMAD6 Gene

Localization for SMAD6 Gene

Subcellular locations from UniProtKB/Swiss-Prot for SMAD6 Gene

Subcellular locations from

Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for SMAD6 gene
Compartment Confidence
nucleus 5
cytosol 5
golgi apparatus 4
plasma membrane 2
extracellular 2
mitochondrion 1

Gene Ontology (GO) - Cellular Components for SMAD6 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005622 intracellular IEA --
GO:0005634 nucleus IDA,IEA 16491121
GO:0005667 transcription factor complex IEA --
GO:0005737 cytoplasm TAS 19018011
GO:0005794 Golgi apparatus IDA --
genes like me logo Genes that share ontologies with SMAD6: view

Pathways & Interactions for SMAD6 Gene

genes like me logo Genes that share pathways with SMAD6: view

Pathways by source for SMAD6 Gene

SIGNOR curated interactions for SMAD6 Gene

Is activated by:
Is inactivated by:

Gene Ontology (GO) - Biological Process for SMAD6 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0001657 ureteric bud development IEA --
GO:0003148 outflow tract septum morphogenesis ISS --
GO:0003170 heart valve development IEA --
GO:0003183 mitral valve morphogenesis ISS --
GO:0003184 pulmonary valve morphogenesis ISS --
genes like me logo Genes that share ontologies with SMAD6: view

Drugs & Compounds for SMAD6 Gene

(5) Drugs for SMAD6 Gene - From: ApexBio and Novoseek

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
Pirfenidone Investigational Pharma TGF-β production inhibitor, Antifibrotic agent; regulates cytokine levels in vivo 55
LDN193189 Hydrochloride Pharma ALK inhibitor,potent and selective 0
LY364947 Pharma 0
RepSox Pharma ALK5 inhibitor,potent and selective, Potent and selective inhibitor of TGF-betaRI 0

(1) Additional Compounds for SMAD6 Gene - From: Novoseek

Name Synonyms Role CAS Number PubChem IDs PubMed IDs

(4) ApexBio Compounds for SMAD6 Gene

Compound Action Cas Number
LDN193189 Hydrochloride ALK inhibitor,potent and selective 1062368-62-0
LY364947 396129-53-6
Pirfenidone TGF-β production inhibitor 53179-13-8
RepSox ALK5 inhibitor,potent and selective 446859-33-2
genes like me logo Genes that share compounds with SMAD6: view

Transcripts for SMAD6 Gene

Unigene Clusters for SMAD6 Gene

SMAD family member 6:
Representative Sequences:

Alternative Splicing Database (ASD) splice patterns (SP) for SMAD6 Gene

No ASD Table

Relevant External Links for SMAD6 Gene

GeneLoc Exon Structure for
ECgene alternative splicing isoforms for

Expression for SMAD6 Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and CGAP SAGE for SMAD6 Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

mRNA differential expression in normal tissues according to GTEx for SMAD6 Gene

This gene is overexpressed in Heart - Atrial Appendage (x5.8) and Lung (x4.7).

Protein differential expression in normal tissues from HIPED for SMAD6 Gene

This gene is overexpressed in Liver (60.5).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, PaxDb, MaxQB, and MOPED for SMAD6 Gene

Protein tissue co-expression partners for SMAD6 Gene

NURSA nuclear receptor signaling pathways regulating expression of SMAD6 Gene:


SOURCE GeneReport for Unigene cluster for SMAD6 Gene:


mRNA Expression by UniProt/SwissProt for SMAD6 Gene:

Tissue specificity: Ubiquitous in various organs, with higher levels in lung. Isoform B is up-regulated in diseased heart tissue.

Evidence on tissue expression from TISSUES for SMAD6 Gene

  • Blood(4.1)
  • Lung(2.5)

Phenotype-based relationships between genes and organs from Gene ORGANizer for SMAD6 Gene

Germ Layers:
  • mesoderm
  • cardiovascular
Head and neck:
  • ear
  • aorta
  • heart
  • heart valve
  • blood
  • blood vessel
genes like me logo Genes that share expression patterns with SMAD6: view

Orthologs for SMAD6 Gene

This gene was present in the common ancestor of animals.

Orthologs for SMAD6 Gene

Organism Taxonomy Gene Similarity Type Details
(Pan troglodytes)
Mammalia SMAD6 34 35
  • 99.26 (n)
(Bos Taurus)
Mammalia SMAD6 34 35
  • 95.36 (n)
(Canis familiaris)
Mammalia SMAD6 34 35
  • 94.02 (n)
(Mus musculus)
Mammalia Smad6 34 16 35
  • 91.12 (n)
(Rattus norvegicus)
Mammalia Smad6 34
  • 90.9 (n)
(Monodelphis domestica)
Mammalia SMAD6 35
  • 83 (a)
(Ornithorhynchus anatinus)
Mammalia SMAD6 35
  • 81 (a)
(Gallus gallus)
Aves SMAD6 34 35
  • 76.97 (n)
(Anolis carolinensis)
Reptilia SMAD6 35
  • 68 (a)
tropical clawed frog
(Silurana tropicalis)
Amphibia Str.2540 34
African clawed frog
(Xenopus laevis)
Amphibia Xl.2593 34
(Danio rerio)
Actinopterygii LOC564395 34
  • 67.44 (n)
smad6a 35
  • 59 (a)
wufk08g05 34
fruit fly
(Drosophila melanogaster)
Insecta Dad 35
  • 24 (a)
(Caenorhabditis elegans)
Secernentea daf-3 35
  • 13 (a)
sea squirt
(Ciona savignyi)
Ascidiacea CSA.9437 35
  • 33 (a)
Species where no ortholog for SMAD6 was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Ashbya gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • alpha proteobacteria (Wolbachia pipientis)
  • amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • baker's yeast (Saccharomyces cerevisiae)
  • barley (Hordeum vulgare)
  • beta proteobacteria (Neisseria meningitidis)
  • bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • common water flea (Daphnia pulex)
  • corn (Zea mays)
  • E. coli (Escherichia coli)
  • filamentous fungi (Aspergillus nidulans)
  • Firmicute bacteria (Streptococcus pneumoniae)
  • fission yeast (Schizosaccharomyces pombe)
  • green algae (Chlamydomonas reinhardtii)
  • honey bee (Apis mellifera)
  • K. lactis yeast (Kluyveromyces lactis)
  • loblloly pine (Pinus taeda)
  • malaria parasite (Plasmodium falciparum)
  • medicago trunc (Medicago Truncatula)
  • moss (Physcomitrella patens)
  • orangutan (Pongo pygmaeus)
  • pig (Sus scrofa)
  • rainbow trout (Oncorhynchus mykiss)
  • rice (Oryza sativa)
  • rice blast fungus (Magnaporthe grisea)
  • schistosome parasite (Schistosoma mansoni)
  • sea anemone (Nematostella vectensis)
  • sea urchin (Strongylocentrotus purpuratus)
  • sorghum (Sorghum bicolor)
  • soybean (Glycine max)
  • stem rust fungus (Puccinia graminis)
  • sugarcane (Saccharum officinarum)
  • thale cress (Arabidopsis thaliana)
  • tomato (Lycopersicon esculentum)
  • toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • wheat (Triticum aestivum)

Evolution for SMAD6 Gene

Gene Tree for SMAD6 (if available)
Gene Tree for SMAD6 (if available)

Paralogs for SMAD6 Gene

Paralogs for SMAD6 Gene

(1) SIMAP similar genes for SMAD6 Gene using alignment to 4 proteins:

genes like me logo Genes that share paralogs with SMAD6: view

Variants for SMAD6 Gene

Sequence variations from dbSNP and Humsavar for SMAD6 Gene

SNP ID Clin Chr 15 pos Sequence Context AA Info Type
rs387907283 Pathogenic, Aortic valve disease 2 (AOVD2) [MIM:614823] 66,781,495(+) CTCCT(G/T)CCCCT nc-transcript-variant, reference, missense
rs387907284 Pathogenic, Aortic valve disease 2 (AOVD2) [MIM:614823] 66,781,288(+) CTCCC(C/G/T)GACGC nc-transcript-variant, reference, missense
rs1057517824 Likely pathogenic 66,781,113(+) GCATC(A/T)TCTAC nc-transcript-variant, reference, missense
rs547033777 Likely benign 66,703,522(+) GGGGG(C/G)CCCCC nc-transcript-variant, upstream-variant-2KB, reference, synonymous-codon
rs565225133 Likely benign 66,703,852(+) TCCCG(C/T)GGCGG nc-transcript-variant, upstream-variant-2KB, reference, synonymous-codon

Structural Variations from Database of Genomic Variants (DGV) for SMAD6 Gene

Variant ID Type Subtype PubMed ID
dgv746e212 CNV loss 25503493
esv3636772 CNV loss 21293372
esv3636773 CNV gain 21293372
nsv827370 CNV gain 20364138

Variation tolerance for SMAD6 Gene

Gene Damage Index Score: 2.71; 46.38% of all genes are more intolerant (likely to be disease-causing)

Relevant External Links for SMAD6 Gene

Human Gene Mutation Database (HGMD)
SNPedia medical, phenotypic, and genealogical associations of SNPs for

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for SMAD6 Gene

Disorders for SMAD6 Gene

MalaCards: The human disease database

(5) MalaCards diseases for SMAD6 Gene - From: OMIM, ClinVar, GeneTests, Orphanet, Swiss-Prot, DISEASES, Novoseek, and GeneCards

Disorder Aliases PubMed IDs
aortic valve disease 2
  • aortic valve stenosis
familial bicuspid aortic valve
brain compression
  • compression of brain
hypoplastic left heart syndrome
  • hlhs
pancreatic cancer
  • pancreatic carcinoma, somatic
- elite association - COSMIC cancer census association via MalaCards
Search SMAD6 in MalaCards View complete list of genes associated with diseases


  • 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. {ECO:0000269 PubMed:22275001}. Note=The disease is caused by mutations 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 (PubMed:22275001). {ECO:0000269 PubMed:22275001}.
  • Note=Rare heterozygous SMAD6 variants, in the presence of a common risk allele (rs1884302) near the BMP2 locus, are strongly associated with non-syndromic midline craniosynostosis and confer a very high risk for disease development. Craniosynostosis is defined as the premature fusion of the cranial sutures, resulting in brain compression and suture-specific craniofacial dysmorphism. {ECO:0000269 PubMed:27606499}.

Relevant External Links for SMAD6

Genetic Association Database (GAD)
Human Genome Epidemiology (HuGE) Navigator
Atlas of Genetics and Cytogenetics in Oncology and Haematology:
genes like me logo Genes that share disorders with SMAD6: view

No data available for Genatlas for SMAD6 Gene

Publications for SMAD6 Gene

  1. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. (PMID: 19211612) Shintani M. … Matsuoka R. (J. Med. Genet. 2009) 3 22 46 64
  2. Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1. (PMID: 16951688) Choi K.C. … Park S.H. (Nat. Immunol. 2006) 3 4 22 64
  3. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. (PMID: 11483516) Itoh F. … Itoh S. (EMBO J. 2001) 3 4 22 64
  4. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. (PMID: 9712726) Afrakhte M. … ten Dijke P. (Biochem. Biophys. Res. Commun. 1998) 3 4 22 64
  5. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. (PMID: 9256479) Topper J.N. … Falb D. (Proc. Natl. Acad. Sci. U.S.A. 1997) 2 3 22 64

Products for SMAD6 Gene

Sources for SMAD6 Gene

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