SMAD9

Summary

SMAD9 (SMAD family member 9, HGNC:6774) is a protein-coding gene on chromosome 13q13.3, encoding SMAD family member 9 (O15198). Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase.

The protein encoded by this gene is a member of the SMAD family, which transduces signals from TGF-beta family members. The encoded protein is activated by bone morphogenetic proteins and interacts with SMAD4. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4093 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 285 total — 15 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_001127217

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6774
Approved symbol	SMAD9
Name	SMAD family member 9
Location	13q13.3
Locus type	gene with protein product
Status	Approved
Aliases	SMAD8, SMAD8/9
Ensembl gene	ENSG00000120693
Ensembl biotype	protein_coding
OMIM	603295
Entrez	4093

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000350148, ENST00000379826, ENST00000399275, ENST00000483941, ENST00000715264, ENST00000871572, ENST00000871573, ENST00000871574, ENST00000871575, ENST00000871576, ENST00000871577, ENST00000871578, ENST00000871579, ENST00000871580, ENST00000871581, ENST00000871582, ENST00000871583, ENST00000927850, ENST00000962417, ENST00000962418, ENST00000962419, ENST00000962420, ENST00000962421

RefSeq mRNA: 3 — MANE Select: NM_001127217 NM_001127217, NM_001378621, NM_005905

CCDS: CCDS45032, CCDS9360

Canonical transcript exons

ENST00000379826 — 7 exons

Exon	Start	End
ENSE00000817120	36865537	36865758
ENSE00000817122	36867273	36867383
ENSE00000817123	36872658	36872915
ENSE00001182807	36879278	36879875
ENSE00001354132	36844831	36848819
ENSE00001775992	36853419	36853675
ENSE00001892819	36920116	36920238

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 97.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.9331 / max 182.4382, expressed in 917 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136803	1.8179	668
136800	0.5895	310
136799	0.4224	211
136801	0.3611	221
136804	0.2792	128
136805	0.1939	106
136798	0.0809	14
136802	0.0697	27
136796	0.0648	16
136795	0.0319	8

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	97.15	gold quality
caput epididymis	UBERON:0004358	95.54	gold quality
urethra	UBERON:0000057	94.92	gold quality
cauda epididymis	UBERON:0004360	93.63	gold quality
seminal vesicle	UBERON:0000998	93.03	gold quality
dorsal root ganglion	UBERON:0000044	92.34	gold quality
trigeminal ganglion	UBERON:0001675	91.31	gold quality
subthalamic nucleus	UBERON:0001906	90.47	gold quality
endometrium	UBERON:0001295	90.30	gold quality
superficial temporal artery	UBERON:0001614	89.08	gold quality
ganglionic eminence	UBERON:0004023	88.77	gold quality
thyroid gland	UBERON:0002046	88.56	gold quality
left lobe of thyroid gland	UBERON:0001120	88.55	gold quality
right lobe of thyroid gland	UBERON:0001119	88.35	gold quality
pons	UBERON:0000988	88.23	gold quality
popliteal artery	UBERON:0002250	88.00	gold quality
tibial artery	UBERON:0007610	87.97	gold quality
corpus callosum	UBERON:0002336	87.53	gold quality
superior vestibular nucleus	UBERON:0007227	87.06	gold quality
parotid gland	UBERON:0001831	86.90	gold quality
tibia	UBERON:0000979	86.77	gold quality
inferior vagus X ganglion	UBERON:0005363	86.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.65	gold quality
aorta	UBERON:0000947	86.25	gold quality
descending thoracic aorta	UBERON:0002345	86.16	gold quality
lower lobe of lung	UBERON:0008949	86.07	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.89	gold quality
ventricular zone	UBERON:0003053	85.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.44	gold quality
synovial joint	UBERON:0002217	85.12	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	46.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
BGLAP	Activation
BMP2
FOXE3	Activation
ID1	Unknown
ID2	Activation
MSX1	Activation
SOST

miRNA regulators (miRDB)

178 targeting SMAD9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AB	99.95	71.31	3488
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-128-3P	99.95	71.17	2484

Literature-anchored findings (GeneRIF, showing 19)

• Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC (PMID:18775991)
• Study described the first mutation in SMAD8 in a patient with IPAH, and suggested the involvement of SMAD8 in the pathogenesis of PAH. (PMID:19211612)
• 5-HT transactivates the serine kinase receptor, BMPR 1A, to activate Smads 1/5/8 via Rho and Rho kinase in in bovine and human pulmonary artery smooth muscle cells (PMID:19244313)
• increases of p16(INK4a) and p21(WAF1/cip1) expression in response to BMP4 were mediated by the Smad1/5/8 signaling pathway. (PMID:19269967)
• Data suggest that Smads 1, 5 and 8 as potential prognostic markers and therapeutic targets for mTOR inhibition therapy of prostate cancer. (PMID:22452883)
• CREBZF, a novel Smad8-binding protein. (PMID:22707059)
• TNF activated NF-kappaB pathway and inhibited the phosphorylation of Smad 1/5/8 and BMP-2-induced osteoblastic differentiation in BMMSCs (PMID:22897816)
• ATP production by NaF promotes hypertrophy-like changes via activation of phospho-Smad8 (PMID:23384547)
• a detailed computational model for TGF-beta signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. (PMID:23804438)
• Case Report: hamartomatous olyposis and gastrointestinal ganglioneuromas with SMAD9 germline mutation that reduces PTEN expression. (PMID:26122142)
• Phosphorylated Smad1/5/8/9 specifically bound to the BREs of Smad8/9 gene. The present study reveals that Smad8/9 is a unique R-Smad regulated through the BMP pathway at the mRNA level. (PMID:26748560)
• Differential expression of TGF-beta superfamily members and role of Smad1/5/9-signalling in chondral versus endochondral chondrocyte differentiation. (PMID:27848974)
• Our results exclude a significant role for the SMAD9v90m mutation in juvenile polyposis syndrome (PMID:28424237)
• Mutations in SMAD9 gene encoding for transforming growth factor (TGF)-[beta] superfamily have been identified in Pulmonary Arterial Hypertension. (PMID:28582316)
• The SNPs of the rs6435156 and rs1048829 locus in the BMPR2 gene, the rs121909287 loci in the ACVRL1 gene, and the rs397514716 locus in the SMAD9 gene were associated with a risk of essential hypertension (EH) in Han Chinese. (PMID:30617053)
• Cyclic AMP appears to promote SMAD1/5/8 pathway activity intracellularly and has the ability to activate canonical SMAD1/5/8 downstream targets. (PMID:30953749)
• A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis. (PMID:31525280)
• Secreted phosphoprotein 24 kD (Spp24) inhibits the growth of human osteosarcoma through the BMP-2/Smad signaling pathway. (PMID:36883270)
• Long noncoding RNA BMPR1B-AS1 stability regulated by IGF2BP2 affects the decidualization in endometriosis patients through the SMAD1/5/9 pathway. (PMID:38703029)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	Mad	FBGN0011648
caenorhabditis_elegans		WBGENE00004856

Paralogs (7): SMAD7 (ENSG00000101665), SMAD5 (ENSG00000113658), SMAD6 (ENSG00000137834), SMAD4 (ENSG00000141646), SMAD3 (ENSG00000166949), SMAD1 (ENSG00000170365), SMAD2 (ENSG00000175387)

Protein

Protein identifiers

SMAD family member 9 — O15198 (reviewed: O15198)

Alternative names: Madh6, Mothers against decapentaplegic homolog 9

All UniProt accessions (2): A0A7I2R5A4, O15198

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-regulated SMAD (R-SMAD).

Subunit / interactions. Interaction with the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit. Interacts with RANBP3L.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in heart, brain, placenta, lung, skeletal muscle, prostate, testis, ovary and small intestine. Also expressed in fetal brain, lung and kidney.

Post-translational modifications. Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase.

Disease relevance. Pulmonary hypertension, primary, 2 (PPH2) [MIM:615342] A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the dwarfin/SMAD family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15198-1	A	yes
O15198-2	B

RefSeq proteins (3): NP_001120689, NP_001365550, NP_005896 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001132	SMAD_dom	Domain
IPR003619	MAD_homology1_Dwarfin-type	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR013019	MAD_homology_MH1	Domain
IPR013790	SMAD/Dwarfins	Family
IPR017855	SMAD-like_dom_sf	Homologous_superfamily
IPR036578	SMAD_MH1_sf	Homologous_superfamily

Pfam: PF03165, PF03166

UniProt features (24 total): strand 7, helix 6, binding site 4, domain 2, chain 1, sequence variant 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6FZT	X-RAY DIFFRACTION	2.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15198-F1	81.90	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 68; 113; 125; 130

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-162582	Signal Transduction
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 164 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, PEREZ_TP63_TARGETS, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_OSTEOBLAST_DIFFERENTIATION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, chr13q13, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOBP_OSSIFICATION, GOBP_RESPONSE_TO_BMP, GOBP_RESPONSE_TO_GROWTH_FACTOR, PEREZ_TP53_AND_TP63_TARGETS, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_TRANSFORMING_GROWTH_FACTOR_BETA_RECEPTOR_SIGNALING_PATHWAY, GOMF_SMAD_BINDING, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN

GO Biological Process (16): osteoblast differentiation (GO:0001649), regulation of transcription by RNA polymerase II (GO:0006357), intracellular iron ion homeostasis (GO:0006879), transforming growth factor beta receptor signaling pathway (GO:0007179), anatomical structure morphogenesis (GO:0009653), cell differentiation (GO:0030154), BMP signaling pathway (GO:0030509), positive regulation of transcription by RNA polymerase II (GO:0045944), SMAD protein signal transduction (GO:0060395), cellular response to BMP stimulus (GO:0071773), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), developmental process (GO:0032502), stem cell differentiation (GO:0048863), cellular response to growth factor stimulus (GO:0071363), transforming growth factor beta receptor superfamily signaling pathway (GO:0141091)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), metal ion binding (GO:0046872), I-SMAD binding (GO:0070411), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), SMAD protein complex (GO:0071141), heteromeric SMAD protein complex (GO:0071144), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell differentiation	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
transforming growth factor beta receptor superfamily signaling pathway	2
regulation of transcription by RNA polymerase II	2
cell surface receptor protein serine/threonine kinase signaling pathway	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
protein-containing complex	2
ossification	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
cellular response to transforming growth factor beta stimulus	1
developmental process	1
anatomical structure development	1
cellular developmental process	1
cellular response to BMP stimulus	1
positive regulation of DNA-templated transcription	1
intracellular signaling cassette	1
cellular response to growth factor stimulus	1
response to BMP	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
biological_process	1
response to growth factor	1
cellular response to endogenous stimulus	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
cation binding	1
SMAD binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD9	SMAD4	Q13485	988
SMAD9	SMAD5	Q99717	958
SMAD9	ACVR1	Q04771	901
SMAD9	BMPR2	Q13873	900
SMAD9	ACVRL1	P37023	897
SMAD9	SMAD3	P84022	821
SMAD9	GDF2	Q9UK05	802
SMAD9	BMP6	P22004	790
SMAD9	ENG	P17813	774
SMAD9	BMP4	P12644	753
SMAD9	ACVR2A	P27037	752
SMAD9	BMPR1A	P36894	746
SMAD9	TGFBR1	P36897	737
SMAD9	TGFB1	P01137	723
SMAD9	BMP2	P12643	719

IntAct

114 interactions, top by confidence:

A	B	Type	Score
SMAD4	SMAD9	psi-mi:“MI:0914”(association)	0.750
SMAD9	SMAD4	psi-mi:“MI:0915”(physical association)	0.750
SMAD4	SMAD9	psi-mi:“MI:0915”(physical association)	0.750
SMAD2	SMAD9	psi-mi:“MI:0914”(association)	0.550
SMAD2	SMAD9	psi-mi:“MI:0915”(physical association)	0.550
SMAD9	LEMD3	psi-mi:“MI:0915”(physical association)	0.550
KDM1A	SMAD9	psi-mi:“MI:0915”(physical association)	0.510
SMAD9	PRMT6	psi-mi:“MI:0915”(physical association)	0.510
SMAD9	LMO4	psi-mi:“MI:0915”(physical association)	0.370
HEYL	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	ZNF557	psi-mi:“MI:0915”(physical association)	0.370
DSTN	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
FLI1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	C10orf2	psi-mi:“MI:0915”(physical association)	0.370
ZEB2	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
TERF1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
SNRNP70	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
HEY1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	TINAGL1	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	SPTBN1	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	CSH1	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	QARS1	psi-mi:“MI:0915”(physical association)	0.370
UBQLN4	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
CXXC5	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
UBQLN1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
PAPPA	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	TRIP12	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (164): SMAD9 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), PSG9 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), SMAD9 (Two-hybrid), SMAD9 (Affinity Capture-MS), SMAD7 (Affinity Capture-Western), SMAD9 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), PSG9 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), DSG4 (Affinity Capture-MS), ZNF143 (Affinity Capture-MS), SMAP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVH6, A0A2K1J5A5, A4H824, A4HWF0, A4IGV6, A6ZMG4, B0QZF7, B3LLZ8, C1IWT1, C7GWA2, C8ZEW0, E9PSU6, O15198, O36398, O55777, P09272, P15130, P23984, P24433, P40688, P48437, P79943, P97440, P97588, Q00111, Q04438, Q06616, Q0ZME3, Q14EA6, Q18LF8, Q1JQA2, Q4JQW6, Q4QFD3, Q4R309, Q5BI31, Q5MQC6, Q6DFB0, Q873B8, Q8NG27, Q8VY64

Diamond homologs: F5GUE5, O15198, O54835, P42003, P45896, P70340, P84022, P84024, P84025, P97454, P97588, Q02330, Q15797, Q1JQA2, Q56I99, Q5R6H7, Q8BUN5, Q99717, Q9I8V2, Q9I962, Q9JIW5, Q9R1V3, Q9W7E7, O35182, O70436, O70437, P45897, P84023, P97471, Q13485, Q15796, Q1HE26, Q1W668, Q21733, Q5R7C0, Q62432, Q95QI7, Q9GKQ9, Q9I9P9, O15105

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
SMAD9	up-regulates	SMAD4	phosphorylation
BMPR1B	up-regulates	SMAD9	phosphorylation
SMURF2	down-regulates	SMAD9	ubiquitination
BMP2	up-regulates	SMAD9
SMURF1	down-regulates	SMAD9	ubiquitination
BMPR1B	“up-regulates activity”	SMAD9	phosphorylation
SMAD9	“form complex”	SMAD8/SMAD4	binding
BMPR1A	“up-regulates activity”	SMAD9	phosphorylation
SMURF	down-regulates	SMAD9	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chromatin organization	7	7.0×	5e-03
Chromatin modifying enzymes	7	6.2×	6e-03
Epigenetic regulation of gene expression	7	6.2×	6e-03
Diseases of signal transduction by growth factor receptors and second messengers	8	5.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

285 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	11
Uncertain significance	121
Likely benign	95
Benign	20

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1179087	NM_001127217.3(SMAD9):c.386dup (p.Tyr129Ter)	Pathogenic
2195334	NM_001127217.3(SMAD9):c.71G>A (p.Trp24Ter)	Pathogenic
2423749	NC_000013.10:g.(?37446775)(37453826_?)del	Pathogenic
2792531	NM_001127217.3(SMAD9):c.686del (p.Leu229fs)	Pathogenic
2892767	NM_001127217.3(SMAD9):c.850C>T (p.Arg284Ter)	Pathogenic
3649577	NM_001127217.3(SMAD9):c.98G>A (p.Trp33Ter)	Pathogenic
3649700	NM_001127217.3(SMAD9):c.199_232del (p.Lys67fs)	Pathogenic
3678444	NM_001127217.3(SMAD9):c.203dup (p.Cys68fs)	Pathogenic
3690588	NM_001127217.3(SMAD9):c.812del (p.Gln271fs)	Pathogenic
3707978	NM_001127217.3(SMAD9):c.668C>G (p.Ser223Ter)	Pathogenic
3716791	NM_001127217.3(SMAD9):c.767del (p.Leu255_Ser256insTer)	Pathogenic
4727900	NM_001127217.3(SMAD9):c.282_283del (p.Trp96fs)	Pathogenic
4755191	NM_001127217.3(SMAD9):c.696dup (p.Ala233fs)	Pathogenic
56970	NM_001127217.3(SMAD9):c.880C>T (p.Arg294Ter)	Pathogenic
6515	NM_001127217.3(SMAD9):c.606C>A (p.Cys202Ter)	Pathogenic
1325103	NM_001127217.3(SMAD9):c.564_567dup (p.Pro190fs)	Likely pathogenic
1330824	NM_001127217.3(SMAD9):c.810_811dup (p.Gln271fs)	Likely pathogenic
3337598	NM_001127217.3(SMAD9):c.1092dup (p.Gln365fs)	Likely pathogenic
3575894	NM_001127217.3(SMAD9):c.1035_1036del (p.Tyr346fs)	Likely pathogenic
3575895	NM_001127217.3(SMAD9):c.1004-2A>G	Likely pathogenic
3575906	NM_001127217.3(SMAD9):c.868C>T (p.Gln290Ter)	Likely pathogenic
3575916	NM_001127217.3(SMAD9):c.671-1G>A	Likely pathogenic
3575925	NM_001127217.3(SMAD9):c.318_322dup (p.Lys108delinsSerTer)	Likely pathogenic
3575928	NM_001127217.3(SMAD9):c.270_276dup (p.Cys93fs)	Likely pathogenic
3575933	NM_001127217.3(SMAD9):c.137dup (p.Lys47fs)	Likely pathogenic
4077556	NM_001127217.3(SMAD9):c.801C>A (p.Tyr267Ter)	Likely pathogenic

SpliceAI

2003 predictions. Top by Δscore:

Variant	Effect	Δscore
13:36848714:T:C	donor_gain	1.0000
13:36853413:CCTTA:C	donor_loss	1.0000
13:36853414:CTTAC:C	donor_loss	1.0000
13:36853415:TTAC:T	donor_loss	1.0000
13:36853416:TACCT:T	donor_loss	1.0000
13:36853417:A:T	donor_loss	1.0000
13:36853418:C:T	donor_loss	1.0000
13:36853672:ACACC:A	acceptor_loss	1.0000
13:36853673:CAC:C	acceptor_gain	1.0000
13:36853676:C:CG	acceptor_loss	1.0000
13:36853677:T:A	acceptor_loss	1.0000
13:36865615:T:A	donor_gain	1.0000
13:36872916:C:CC	acceptor_gain	1.0000
13:36876314:ACACT:A	donor_gain	1.0000
13:36876315:CACTC:C	donor_gain	1.0000
13:36876318:T:A	donor_gain	1.0000
13:36920114:A:AC	donor_gain	1.0000
13:36920115:C:CC	donor_gain	1.0000
13:36920115:CTG:C	donor_gain	1.0000
13:36853417:A:AC	donor_gain	0.9900
13:36853418:C:CC	donor_gain	0.9900
13:36853432:AT:A	donor_gain	0.9900
13:36853671:CACAC:C	acceptor_gain	0.9900
13:36853672:ACAC:A	acceptor_gain	0.9900
13:36853673:CACC:C	acceptor_gain	0.9900
13:36853674:AC:A	acceptor_gain	0.9900
13:36853675:CC:C	acceptor_gain	0.9900
13:36853676:C:CC	acceptor_gain	0.9900
13:36865535:AC:A	donor_gain	0.9900
13:36865536:CC:C	donor_gain	0.9900

AlphaMissense

3066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:36848722:A:G	L453P	1.000
13:36848734:A:G	L449P	1.000
13:36848738:A:G	W448R	1.000
13:36848738:A:T	W448R	1.000
13:36848743:A:G	L446P	1.000
13:36848769:C:A	W437C	1.000
13:36848769:C:G	W437C	1.000
13:36848771:A:G	W437R	1.000
13:36848771:A:T	W437R	1.000
13:36848772:G:C	C436W	1.000
13:36848773:C:T	C436Y	1.000
13:36848774:A:G	C436R	1.000
13:36848776:G:T	P435H	1.000
13:36848788:A:T	V431D	1.000
13:36848798:G:C	R428G	1.000
13:36848798:G:T	R428S	1.000
13:36848803:T:C	Y426C	1.000
13:36848804:A:G	Y426H	1.000
13:36848812:C:A	G423V	1.000
13:36848812:C:T	G423D	1.000
13:36848813:C:A	G423C	1.000
13:36848813:C:G	G423R	1.000
13:36848814:C:A	W422C	1.000
13:36848814:C:G	W422C	1.000
13:36848815:C:G	W422S	1.000
13:36848816:A:G	W422R	1.000
13:36848816:A:T	W422R	1.000
13:36848818:C:T	G421D	1.000
13:36848819:C:G	G421R	1.000
13:36853419:C:A	K420N	1.000

dbSNP variants (sampled 300 via entrez): RS1000053321 (13:36898214 T>C,G), RS1000056856 (13:36844835 A>G), RS1000098783 (13:36854096 T>C,G), RS1000102852 (13:36921829 C>T), RS1000125415 (13:36892670 A>G), RS1000146955 (13:36871316 G>A,C), RS1000237462 (13:36892909 A>G), RS1000257417 (13:36886652 A>C), RS1000285185 (13:36920041 C>A,G,T), RS1000334865 (13:36886864 G>A), RS1000337067 (13:36919913 C>T), RS1000337832 (13:36853995 C>T), RS1000338696 (13:36881537 A>G), RS1000420151 (13:36865276 C>T), RS1000432096 (13:36881864 A>T)

Disease associations

OMIM: gene MIM:603295 | disease phenotypes: MIM:615342, MIM:211980

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary hypertension, primary, 2	Strong	Autosomal dominant
heritable pulmonary arterial hypertension	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pulmonary arterial hypertension	Definitive	AD

Mondo (3): pulmonary hypertension, primary, 2 (MONDO:0014134), lung cancer (MONDO:0008903), heritable pulmonary arterial hypertension (MONDO:0017148)

Orphanet (2): Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Pulmonary arterial hypertension associated with congenital heart disease (Orphanet:275803)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002092	Pulmonary arterial hypertension
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0003829	Typified by incomplete penetrance
HP:0005317	Increased pulmonary vascular resistance
HP:0031687	Abnormally loud pulmonic component of the second heart sound

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002751_4	Spontaneous preterm birth (preterm birth)	8.000000e-06
GCST002892_13	Perioperative myocardial infarction in coronary artery bypass surgery	6.000000e-06
GCST005194_198	Coronary artery disease	2.000000e-06
GCST005348_35	Total body bone mineral density	1.000000e-08
GCST006288_156	Heel bone mineral density	2.000000e-06
GCST006288_23	Heel bone mineral density	1.000000e-10
GCST006979_1095	Heel bone mineral density	7.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006917	spontaneous preterm birth
EFO:0006921	birth measurement
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
sodium arsenite	affects methylation, increases expression	3
Benzo(a)pyrene	increases expression, decreases expression, decreases methylation	3
aristolochic acid I	decreases expression, decreases reaction	2
methylmercuric chloride	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
dorsomorphin	decreases reaction, increases phosphorylation, affects cotreatment, decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
aucubin	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	decreases expression, increases expression	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
sirtinol	decreases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	decreases expression	1
LDN 193189	decreases reaction, increases phosphorylation	1
Resveratrol	increases phosphorylation	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects expression	1
Cadmium	decreases expression	1
Caffeine	affects phosphorylation	1
Diethylhexyl Phthalate	decreases expression	1
Diethylstilbestrol	decreases expression	1
Succimer	affects cotreatment, decreases expression	1

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3HN	Abcam HEK293T SMAD9 KO	Transformed cell line	Female
CVCL_D8VM	Ubigene HCT 116 SMAD9 KO	Cancer cell line	Male
CVCL_D9SC	Ubigene HEK293 SMAD9 KO	Transformed cell line	Female
CVCL_E0PE	Ubigene HeLa SMAD9 KO	Cancer cell line	Female

Clinical trials (associated diseases)

305 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial
NCT00158041	PHASE4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	PHASE4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	PHASE4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	PHASE4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	PHASE4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	PHASE4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	PHASE4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	PHASE4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	PHASE4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	PHASE4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	PHASE4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	PHASE4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	PHASE4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	PHASE4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	PHASE4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	PHASE4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	PHASE4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	PHASE4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	PHASE4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	PHASE4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	PHASE4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	PHASE4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	PHASE4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	PHASE4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	PHASE4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	PHASE4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	PHASE4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	PHASE4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	PHASE4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	PHASE4	NOT_YET_RECRUITING	A Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471	PHASE4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00002550	PHASE3	COMPLETED	Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00002583	PHASE3	COMPLETED	Vinorelbine + Cisplatin or No Further Therapy in Non-small Cell Lung Cancer That Has Been Surgically Removed