SMAD3

Chr 15AD

SMAD family member 3

Also known as: HSPC193, HsT17436, JV15-2, LDS1C, LDS3, MADH3, hMAD-3, hSMAD3

NCBI Gene: 4088ENSG00000166949UniProt: P84022

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]

Primary Disease Associations & Inheritance

Loeys-Dietz syndrome 3MIM #613795
AD
UniProtColorectal cancer
685
ClinVar variants
121
Pathogenic / LP
0.80
pLI score
2
Active trials
Clinical Summary— SMAD3
🧬
Gene-Disease Validity (ClinGen)
aneurysm-osteoarthritis syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
121 Pathogenic / Likely Pathogenic· 328 VUS of 685 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.40LOEUF
pLI 0.798
Z-score 3.66
OE 0.17 (0.09–0.40)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.48Z-score
OE missense 0.38 (0.33–0.46)
97 obs / 252.5 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.09–0.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.38 (0.33–0.46)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.12
0≤1.21.6
LoF obs/exp: 4 / 22.9Missense obs/exp: 97 / 252.5Syn Z: -0.96

ClinVar Variant Classifications

685 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic52
VUS328
Likely Benign205
Benign8
Conflicting23
69
Pathogenic
52
Likely Pathogenic
328
VUS
205
Likely Benign
8
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
35
5
29
0
69
Likely Pathogenic
26
16
10
0
52
VUS
3
274
47
4
328
Likely Benign
0
0
89
116
205
Benign
0
0
8
0
8
Conflicting
—23
Total64295183120685

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SMAD3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SMAD3-related Loeys-Dietz syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Loeys-Dietz syndrome 3

MIM #613795

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SMAD3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts.
Guo DZ et al.·Mol Cancer
2024
Macrophages: versatile players in renal inflammation and fibrosis.
Tang PM et al.·Nat Rev Nephrol
2019Review
Smad3 Signatures in Renal Inflammation and Fibrosis.
Wu W et al.·Int J Biol Sci
2022Review
Btg2 Promotes Focal Segmental Glomerulosclerosis via Smad3-Dependent Podocyte-Mesenchymal Transition.
Dan Hu Q et al.·Adv Sci (Weinh)
2023
Diverse roles of TGF-β/Smads in renal fibrosis and inflammation.
Lan HY·Int J Biol Sci
2011Review
Endothelial-to-Mesenchymal Transition Contributes to Accelerated Atherosclerosis in Hutchinson-Gilford Progeria Syndrome.
Hamczyk MR et al.·Circulation
2024
A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.
Schepers D et al.·Hum Mutat
2018
Knocking out USP7 attenuates cardiac fibrosis and endothelial-to-mesenchymal transition by destabilizing SMAD3 in mice with heart failure with preserved ejection fraction.
Yuan S et al.·Theranostics
2024
Modulation of transforming growth factor-β-induced kidney fibrosis by leucine-rich ⍺-2 glycoprotein-1.
Hong Q et al.·Kidney Int
2022
Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders.
Overwater E et al.·Hum Mutat
2018Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SMC4/SMAD3/NF-κB axis drives cervical cancer progression and radioresistance via DNA damage repair and immune modulation.
Wu H et al.·J Transl Med
2026
Aconiti Lateralis Radix Praeparata active ingredients of Heishunpian potential on LPS-induced Nrf-2/NQO1/HO-1 and Smad3/Akt/p38 signalling pathways in chronic obstructive pulmonary disease: a network pharmacology study.
Wang Y et al.·J Mol Histol
2026
Ectopic CD11c Drives SMAD3-Mediated Aberrant Antigen Presentation and Epithelial-Mesenchymal Transition in Esophageal Squamous Cell Carcinoma.
Liao H et al.·Cancer Commun (Lond)
2026🔓 Open Access
Huanggan decoction ameliorates cholestatic hepatic fibrosis in rats via TGF-β1/Smad3 signaling pathway.
Lei Y et al.·PLoS One
2026🔓 Open Access
γ-Glutamylcyclotransferase Depletion Induces p15INK4b and p21Cip1-mediated Senescence via TGF-β2/SMAD3 Pathway Activation in Breast Cancer Cells.
Kubota S et al.·Cancer Genomics Proteomics
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Emphysema

Characterizing Matrix Metalloproteinase-12 (MMP12) in Sputum

RECRUITING
NCT04761393McMaster UniversityStarted 2022-11-29
Hyperpolarized 129Xe (Xenon) diffusion-weighted MRI
Rectal Cancer

Study of the Predictive and Prognostic Role of Pharmacogenetic and Radiogenic Variants on the Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer

NOT YET RECRUITING
NCT06616870Centro di Riferimento Oncologico - AvianoStarted 2024-10-03

External Resources

Links to major genomics databases and tools