rs35874463

This is a variant in the SMAD3 gene that changes a isoleucine to an valine.

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GWAS Catalog Trait Associations (13)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

health trait

Schoeler T et al. “Combining cross-sectional and longitudinal genomic approaches to identify determinants of cognitive and physical decline.” Nature Communications 16(1):4524 (2025)
Allele A
OR 0.03
p 2.0e-31
N 405,979
Large GWAS
European

BMI-adjusted hip circumference

Christakoudi S et al. “GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer.” Scientific Reports 11(1):10688 (2021)
Allele G
OR 0.07
p 4.0e-25
N 186,825
Major Consortium StudyLarge GWAS
European

BMI-adjusted waist circumference

Christakoudi S et al. “GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer.” Scientific Reports 11(1):10688 (2021)
Allele G
OR 0.07
p 1.0e-23
N 186,825
Major Consortium StudyLarge GWAS
European

lean body mass

Harris BHL et al. “New role of fat-free mass in cancer risk linked with genetic predisposition.” Scientific Reports 14(1):7270 (2024)
Allele G
OR 0.02
p 1.0e-13
N 337,739
Large GWAS
European

base metabolic rate measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele G
OR 0.02
p 2.0e-12
N 394,642
Large GWAS
European

appendicular lean mass

Pei YF et al. “The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study.” Communications Biology 3(1):608 (2020)
Allele A
OR 0.03
p 3.0e-12
N 450,243
Major Consortium StudyLarge GWAS
European

cardiovascular measurement

Kany S et al. “Multitrait analyses identify genetic variants associated with aortic valve function and aortic stenosis risk.” Nature Genetics 58(1):47-56 (2026)
Allele A
OR 0.06
p 5.0e-11
N 96,385
Large GWAS
European

atrial fibrillation

Yuan S et al. “Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation.” Nature Communications 16(1):6426 (2025)
Allele A
OR 0.05
p 2.0e-10
N 2,584,013
Large GWAS
multi-ancestry

aortic stenosis

Kany S et al. “Multitrait analyses identify genetic variants associated with aortic valve function and aortic stenosis risk.” Nature Genetics 58(1):47-56 (2026)
Allele A
OR 0.02
p 1.0e-9
N 205,483
Large GWAS
European
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ClinVar annotation

Likely Benign★★★☆
21 submitters3 publications

Aneurysm-osteoarthritis syndrome; Ehlers-Danlos syndrome (EDS); Familial thoracic aortic aneurysm and aortic dissection (TAAD); Loeys-Dietz syndrome (LDS); Thoracic aortic aneurysm; not specified

View on ClinVar →
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Research that mentions this SNP (2)

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SNP–SNP interactions between DNA repair genes were associated with breast cancer risk in a Korean population
AssociationN=1,659Wonshik Han et al.(2012)· Cancer

This dissertation investigated sex differences in melanoma using Connecticut Tumor Registry and Minnesota Skin Health study cohorts. Multiple SNPs in DNA repair genes (RFC1, ERCC4, ERCC5, ERCC6, PARP1, FBRSL1) and immune response genes (SMAD3, CXCL8, IFNγ, IL-17A) were associated with Breslow thickness and interacted with UV exposure to modify melanoma progression. Notably, rs4253114 (ERCC6) was the only SNP significant in both male and female sex-stratified analyses. UV exposure showed opposite effects between sexes: inversely associated with male mortality (HR 0.5-0.9 range) but not associated with female survival; skin awareness reduced Breslow thickness in females but not males.

Traits studied:Breslow thicknessMelanomaMelanoma progressionMelanoma survival
PubMedDOIMetascience Observatory
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Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population
AssociationN=7,457Maarit Lappalainen et al.(2008)· Inflammatory Bowel Diseases

PhD thesis describing comprehensive genome-wide association studies of acute anterior uveitis (AAU) in European (2,752 cases, 3,836 controls) and East Asian (821 cases, 4,898 controls) populations. European descent GWAS identified HLA-B at genome-wide significance plus 11 suggestive loci (ERAP1, NOS2, MERTK). East Asian GWAS identified HLA-B and ERAP1 at genome-wide significance plus 12 suggestive loci (GPR68, RHBDD2). Mendelian randomization confirmed ERAP1 as functionally relevant and showed genetically predicted CRP levels positively associated with AAU risk.

Traits studied:Acute anterior uveitis (AAU)Ankylosing spondylitis (AS)Spondyloarthropathies
PubMedDOIMetascience Observatory

About SMAD3

The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

View all SMAD3 variants →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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