SMAD2

Chr 18AD

SMAD family member 2

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

NCBI Gene: 4087ENSG00000175387UniProt: Q15796OMIM: 601366

The SMAD2 protein is an intracellular signal transducer and transcriptional modulator that mediates TGF-beta and activin signaling pathways, regulating cellular processes including proliferation, apoptosis, and differentiation. Mutations cause autosomal dominant Loeys-Dietz syndrome 6 and congenital heart defects with or without heterotaxy, primarily affecting cardiovascular and connective tissue systems. The gene is highly constrained against loss-of-function variants (pLI 0.997, LOEUF 0.259), indicating that such mutations are likely to cause significant developmental effects.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.262 OMIM phenotypes
Clinical Summary— SMAD2
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Gene-Disease Validity (ClinGen)
congenital heart disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.
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ClinVar Variants
7 unique Pathogenic / Likely Pathogenic· 45 VUS of 99 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — SMAD2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
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
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
LoF OE0.10 (0.04–0.26)
0≤0.351.4
Missense OE0.35 (0.29–0.42)
0≤0.61.4
Synonymous OE1.09
0≤1.21.6
LoF obs/exp: 3 / 30.0Missense obs/exp: 88 / 251.4Syn Z: -0.66
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedSMAD2-related congenital heart diseaseLOFAD
DN
0.3991th %ile
GOF
0.4184th %ile
LOF
0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 71% of P/LP variants are LoF · LOEUF 0.26

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

99 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic3
VUS45
Likely Benign27
Benign2
4
Pathogenic
3
Likely Pathogenic
45
VUS
27
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
1
0
4
Likely Pathogenic
2
0
1
0
3
VUS
0
39
6
0
45
Likely Benign
0
0
11
16
27
Benign
0
0
2
0
2
Total539211681

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients