SMAD2

Chr 18

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]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCongenital heart defects, multiple types, 8, with or without heterotaxy
UniProtLoeys-Dietz syndrome 6

Clinical highlights

Gene-disease validity (ClinGen)
congenital heart disease · ADDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total
Interpreting a novel variant
Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.
2
Active trials
1127
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.26
LOEUF· LoF intol.
LOF
Mechanism· G2P
📖
GeneReview available — SMAD2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.10 (0.04–0.26)
0≤0.351.4
Missense OE?0.35 (0.29–0.42)
0≤0.61.4
Synonymous OE?1.09
0≤1.21.6
LoF obs/exp: 3 / 30.0Missense obs/exp: 88 / 251.4Syn Z: -0.66

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

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