SMAD2

Chr 18AD

SMAD family member 2

Also known as: CHTD8, JV18, JV18-1, LDS6, MADH2, MADR2, hMAD-2, hSMAD2

NCBI Gene: 4087ENSG00000175387UniProt: Q15796

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. [provided by RefSeq, May 2012]

Primary Disease Associations & Inheritance

Congenital heart defects, multiple types, 8, with or without heterotaxyMIM #619657
AD
Loeys-Dietz syndrome 6MIM #619656
AD
533
ClinVar variants
77
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— SMAD2
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
77 Pathogenic / Likely Pathogenic· 206 VUS of 533 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
Dual constrained — LoF & missense intolerant
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.
0.26LOEUF
pLI 0.997
Z-score 4.57
OE 0.10 (0.04–0.26)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.66Z-score
OE missense 0.35 (0.29–0.42)
88 obs / 251.4 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.0.10 (0.04–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.35 (0.29–0.42)
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.1.09
0≤1.21.6
LoF obs/exp: 3 / 30.0Missense obs/exp: 88 / 251.4Syn Z: -0.66

ClinVar Variant Classifications

533 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic16
VUS206
Likely Benign219
Benign29
Conflicting2
61
Pathogenic
16
Likely Pathogenic
206
VUS
219
Likely Benign
29
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
6
46
0
61
Likely Pathogenic
6
5
5
0
16
VUS
3
172
30
1
206
Likely Benign
0
0
82
137
219
Benign
0
0
27
2
29
Conflicting
—2
Total18183190140533

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

View in ClinVar →

Protein Context — Lollipop Plot

SMAD2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SMAD2-related congenital heart disease

limited
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

Congenital heart defects, multiple types, 8, with or without heterotaxy

MIM #619657

Molecular basis of disorder known

Autosomal dominant

Loeys-Dietz syndrome 6

MIM #619656

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SMAD2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New insights into TGF-β/Smad signaling in tissue fibrosis.
Hu HH et al.·Chem Biol Interact
2018Review
Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease.
Kimura K et al.·Nature
2025
Diverse roles of TGF-β/Smads in renal fibrosis and inflammation.
Lan HY·Int J Biol Sci
2011Review
A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.
Schepers D et al.·Hum Mutat
2018
A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
Loeys BL et al.·Nat Genet
2005
Molecular mechanisms of cancer cachexia-related loss of skeletal muscle mass: data analysis from preclinical and clinical studies.
Martin A et al.·J Cachexia Sarcopenia Muscle
2023Review
Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways.
Lv Q et al.·Mol Med
2020
Conditioned medium of human bone marrow-derived stem cells promotes tendon-bone healing of the rotator cuff in a rat model.
Chen W et al.·Biomaterials
2021Functional
M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway.
Yin H et al.·Cell Death Differ
2023
[Colorectal oncogenesis].
Laurent-Puig P et al.·Bull Cancer
2010Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
[Retracted] MicroRNA‑486‑5p inhibits the growth of human hypertrophic scar fibroblasts by regulating Smad2 expression.
Shi Y et al.·Mol Med Rep
2026🔓 Open Access
Inhalable Albumin Nanoparticles Co-Delivering Dihydroartemisinin and Nintedanib Attenuate Pulmonary Fibrosis by Suppressing TGF-β1/Smad2/3 Signaling.
Zheng C et al.·Int J Nanomedicine
2026🔓 Open Access
PKM2-DNMT3A-SMAD2 Axis Regulates Cell Proliferation via Histone Lactylation in Breast Cancer.
Sabu A et al.·Mol Cell Biol
2026
Efficient Inhibition of TGF-β Signaling via Cytosolic Delivery of a Smad2/3-Binding Peptide Using the Cell-Penetrating PG-Surfactant DKDKC12-K5 to Block Smad2/3 Nuclear Translocation.
Suzuki R et al.·Bioconjug Chem
2026
[Corrigendum] Hsa_circularRNA_0079201 suppresses chondrocyte proliferation and endochondral ossification by regulating the microRNA‑140‑3p/SMAD2 signaling pathway in idiopathic short stature.
Liu X et al.·Int J Mol Med
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
ALS (Amyotrophic Lateral Sclerosis)

This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling

NOT YET RECRUITING
NCT07321860Phase PHASE2, PHASE3Gipfel Life Sciences GmbHStarted 2026-06-30
Galunisertib + Nerandomilast Combination
Emphysema

Characterizing Matrix Metalloproteinase-12 (MMP12) in Sputum

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

External Resources

Links to major genomics databases and tools