SMAD9

Chr 13AD

SMAD family member 9

Also known as: MADH6, MADH9, PPH2, SMAD8, SMAD8/9, SMAD8A, SMAD8B

NCBI Gene: 4093ENSG00000120693UniProt: O15198OMIM: 603295

The encoded protein is a transcriptional modulator that transduces signals from bone morphogenetic proteins (BMPs) and interacts with SMAD4 in the TGF-beta signaling pathway. Mutations cause primary pulmonary hypertension type 2 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating intolerance to haploinsufficiency.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.851 OMIM phenotype
Clinical Summary— SMAD9
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Gene-Disease Validity (ClinGen)
pulmonary arterial hypertension · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
79 unique Pathogenic / Likely Pathogenic· 129 VUS of 342 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — SMAD9
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.85LOEUF
pLI 0.000
Z-score 2.06
OE 0.50 (0.31–0.85)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.52Z-score
OE missense 0.91 (0.82–1.01)
248 obs / 272.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.50 (0.31–0.85)
0≤0.351.4
Missense OE0.91 (0.82–1.01)
0≤0.61.4
Synonymous OE1.12
0≤1.21.6
LoF obs/exp: 10 / 19.9Missense obs/exp: 248 / 272.2Syn Z: -1.03
DN
0.6161th %ile
GOF
0.3789th %ile
LOF
0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
LOF35% of P/LP variants are LoF
GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFExome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation.PMID:26122142

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

342 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64
Likely Pathogenic15
VUS129
Likely Benign101
Benign20
Conflicting9
64
Pathogenic
15
Likely Pathogenic
129
VUS
101
Likely Benign
20
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
51
0
64
Likely Pathogenic
15
0
0
0
15
VUS
2
112
14
1
129
Likely Benign
0
5
26
70
101
Benign
0
1
15
4
20
Conflicting
—9
Total3011810675338

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

View in ClinVar →

Protein Context — Lollipop Plot

SMAD9 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
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
RNA-seq at different stages of human pancreatic β cell differentiation reveals proliferation dynamics and SMAD9 in directing β cell fate.
Lim EXH et al.·Cell Death Dis
2026Open Access
Dose-optimized HILT promotes peripheral nerve repair through BMP4-Smad9-mediated inhibition of neuroinflammation and oxidative stress.
Gong L et al.·APL Bioeng
2026Open Access
Exosomal circZNF638 promotes postmenopausal osteoporosis progression through MGAT1-mediated SMAD9 glycosylation.
Luo Y et al.·Connect Tissue Res
2026
A novel SMAD9 nonsense variant in an 11-year-old Japanese patient with diffuse pulmonary arteriovenous malformation: A case report.
Asai Y et al.·J Cardiol Cases
2025Case report
The human SMAD9 (GCC) repeat links to natural selection and late-onset neurocognitive disorders.
Alizadeh S et al.·Neurol Sci
2024
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