SMAD2

SMAD family member 2, the group of SMAD family

Basic information

Region (hg38): 18:47808957-47931146

Previous symbols: [ "MADH2" ]

Links

ENSG00000175387 ∙ NCBI:4087 ∙ OMIM:601366 ∙ HGNC:6768 ∙ Uniprot:Q15796 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Loeys-Dietz syndrome (Strong), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Supportive), mode of inheritance: AD
• congenital heart disease (Moderate), mode of inheritance: AD
• Loeys-Dietz syndrome 6 (Moderate), mode of inheritance: AD
• congenital heart defects, multiple types, 8, with or without heterotaxy (Limited), mode of inheritance: AD
• Loeys-Dietz syndrome 6 (Strong), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Moderate), mode of inheritance: AD
• congenital heart disease (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Loeys-Dietz syndrome 6; Congenital heart defects, multiple types, 8, with or without heterotaxy	AD	Cardiovascular	Loeys-Dietz syndrome can involve cardiovascular sequelae, including aortic aneurysms and dissection, and awareness may allow early detection and medical and surgical management; Congenital heart defects, multiple types, 8, with or without heterotaxy can involve congenital heart anomalies, and awareness may allow early detection and management	Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal	23665959; 26247899; 28283438,; 29967133; 30157302

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMAD2 gene.

• not provided (8 variants)
• Congenital heart defects, multiple types, 8, with or without heterotaxy (3 variants)
• Loeys-Dietz syndrome 6 (2 variants)
• Inborn genetic diseases (2 variants)
• SMAD2-related cardiac disorders (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMAD2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	86	1	89
missense	5	3	87			95
nonsense	2	2	3			7
start loss						0
frameshift	5	2	3			10
inframe indel			3			3
splice donor/acceptor (+/-2bp)	1		1			2
splice region			7	14		21
non coding			1	50	26	77
Total	13	7	100	136	27

Variants in SMAD2

This is a list of pathogenic ClinVar variants found in the SMAD2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
18-47841734-T-C			Likely benign (Dec 05, 2018)
18-47841832-A-G		Neoplasm	- (-)
18-47841843-CA-C			Uncertain significance (Apr 14, 2021)
18-47841846-C-T			Uncertain significance (Aug 15, 2019)
18-47841847-G-A		Loeys-Dietz syndrome 6	Uncertain significance (Jun 05, 2023)
18-47841848-C-A		Inborn genetic diseases	Likely benign (Oct 09, 2023)
18-47841851-T-C			Uncertain significance (Jan 23, 2024)
18-47841853-A-T		Inborn genetic diseases	Uncertain significance (Mar 20, 2023)
18-47841854-AG-A			Uncertain significance (Jul 01, 2022)
18-47841855-G-A			Uncertain significance (Jan 09, 2023)
18-47841857-G-T		Inborn genetic diseases	Likely benign (Nov 04, 2022)
18-47841862-C-T		Loeys-Dietz syndrome 6	Pathogenic (May 21, 2022)
18-47841866-CTGAGT-C			Uncertain significance (Aug 15, 2022)
18-47841883-C-T			Uncertain significance (Sep 06, 2021)
18-47841885-A-G		Loeys-Dietz syndrome 6	Pathogenic (Dec 10, 2021)
18-47841902-A-G		Inborn genetic diseases	Likely benign (Dec 29, 2021)
18-47841906-A-C			Pathogenic (May 31, 2023)
18-47841909-T-G			Uncertain significance (Jan 25, 2022)
18-47841913-G-A			Uncertain significance (Apr 07, 2023)
18-47841923-G-A		Inborn genetic diseases	Likely benign (Sep 13, 2022)
18-47841927-G-C		SMAD2-related disorder	Uncertain significance (Jan 06, 2024)
18-47841934-T-C			Uncertain significance (Dec 19, 2022)
18-47841934-T-G			Uncertain significance (Sep 09, 2022)
18-47841937-T-G			Uncertain significance (May 30, 2023)
18-47841941-C-T		Inborn genetic diseases	Likely benign (Jan 22, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMAD2	protein_coding	protein_coding	ENST00000402690	10	99594

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00339	125736	0	4	125740	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.66	88	251	0.350	0.0000132	3033
Missense in Polyphen		16	87.809	0.18221		1154
Synonymous	-0.656	98	90.1	1.09	0.00000500	890
Loss of Function	4.57	3	30.0	0.100	0.00000181	313

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000265	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:9892009}.
• Pathway: Gastric cancer - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);TGF-beta signaling pathway - Homo sapiens (human);Adherens junction - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Cell cycle - Homo sapiens (human);Endocytosis - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);EGF-Core;WNT-Core;TGF-Core;AGE-RAGE pathway;Endoderm Differentiation;Mesodermal Commitment Pathway;Extracellular vesicle-mediated signaling in recipient cells;TGF-beta Signaling Pathway;Hypothesized Pathways in Pathogenesis of Cardiovascular Disease;Tgif disruption of Shh signaling;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;TGF-B Signaling in Thyroid Cells for Epithelial-Mesenchymal Transition;Canonical and Non-Canonical TGF-B signaling;Protein alkylation leading to liver fibrosis;Chromosomal and microsatellite instability in colorectal cancer;EMT transition in Colorectal Cancer;TGF-beta Receptor Signaling;Developmental Biology;Disease;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Signaling by Activin;Alpha6Beta4Integrin;Post-translational protein modification;Metabolism of proteins;RNA Polymerase II Transcription;SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription;Downregulation of SMAD2/3:SMAD4 transcriptional activity;TGF-beta super family signaling pathway canonical;Signaling by NODAL;TGF_beta_Receptor;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;EGFR1;tgf beta signaling pathway;Ub-specific processing proteases;Deubiquitination;Transcriptional regulation of pluripotent stem cells;SMAD2/3 Phosphorylation Motif Mutants in Cancer;SMAD2/3 MH2 Domain Mutants in Cancer;Loss of Function of SMAD2/3 in Cancer;Signaling by TGF-beta Receptor Complex in Cancer;Signaling by TGF-beta Receptor Complex;BMP2 signaling TGF-beta MV;Signaling by TGF-beta family members;BMP signaling Dro;Downregulation of TGF-beta receptor signaling;TGF-beta receptor signaling activates SMADs;Diseases of signal transduction;Validated targets of C-MYC transcriptional repression;Glypican 1 network;Regulation of cytoplasmic and nuclear SMAD2/3 signaling;Regulation of nuclear SMAD2/3 signaling;TGF-beta receptor signaling (Consensus)

Recessive Scores

• pRec: 0.844

Intolerance Scores

• loftool: 0.173
• rvis_EVS: -0.38
• rvis_percentile_EVS: 27.42

Haploinsufficiency Scores

• pHI: 1.00
• hipred: Y
• hipred_score: 0.825
• ghis: 0.685

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Smad2
• Phenotype: endocrine/exocrine gland phenotype; taste/olfaction phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; neoplasm; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: smad2
• Affected structure: neuron
• Phenotype tag: abnormal
• Phenotype quality: degenerate

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;ureteric bud development;in utero embryonic development;endoderm formation;mesoderm formation;transforming growth factor beta receptor signaling pathway;common-partner SMAD protein phosphorylation;SMAD protein complex assembly;zygotic specification of dorsal/ventral axis;gastrulation;negative regulation of cell population proliferation;response to glucose;post-embryonic development;anterior/posterior pattern specification;positive regulation of epithelial to mesenchymal transition;protein deubiquitination;regulation of transforming growth factor beta receptor signaling pathway;signal transduction involved in regulation of gene expression;insulin secretion;lung development;adrenal gland development;negative regulation of transforming growth factor beta receptor signaling pathway;positive regulation of BMP signaling pathway;pancreas development;primary miRNA processing;activin receptor signaling pathway;somatic stem cell population maintenance;organ growth;intracellular signal transduction;nodal signaling pathway;wound healing;cell fate commitment;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;paraxial mesoderm morphogenesis;embryonic foregut morphogenesis;embryonic cranial skeleton morphogenesis;regulation of binding;pericardium development;SMAD protein signal transduction;secondary palate development;response to cholesterol;positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;cytoplasm;cytosol;activin responsive factor complex;protein-containing complex;SMAD protein complex;heteromeric SMAD protein complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;chromatin binding;double-stranded DNA binding;DNA-binding transcription factor activity;transforming growth factor beta receptor binding;protein binding;transcription factor binding;phosphatase binding;transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity;ubiquitin protein ligase binding;activating transcription factor binding;type I transforming growth factor beta receptor binding;enhancer binding;protein homodimerization activity;SMAD binding;metal ion binding;protein heterodimerization activity;tau protein binding;co-SMAD binding;I-SMAD binding;R-SMAD binding;primary miRNA binding;disordered domain specific binding