SMAD4

Summary

SMAD4 (SMAD family member 4, HGNC:6770) is a protein-coding gene on chromosome 18q21.2, encoding SMAD family member 4 (Q13485). In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. In precision oncology, SMAD4 Underexpression confers sensitivity to Gemcitabine in Lung Non-small Cell Carcinoma (CIViC Level B); 3 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome.

Source: NCBI Gene 4089 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Myhre syndrome (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 2,620 total — 240 pathogenic, 55 likely-pathogenic
• Phenotypes (HPO): 242
• Druggable target: yes
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 18 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 157 downstream targets (CollecTRI)
• MANE Select transcript: NM_005359

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6770
Approved symbol	SMAD4
Name	SMAD family member 4
Location	18q21.2
Locus type	gene with protein product
Status	Approved
Aliases	DPC4
Ensembl gene	ENSG00000141646
Ensembl biotype	protein_coding
OMIM	600993
Entrez	4089

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 25 protein_coding, 13 retained_intron, 10 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000342988, ENST00000398417, ENST00000585448, ENST00000586253, ENST00000588745, ENST00000588860, ENST00000589076, ENST00000589706, ENST00000589941, ENST00000590061, ENST00000590499, ENST00000591126, ENST00000592186, ENST00000592911, ENST00000593223, ENST00000611848, ENST00000684953, ENST00000685090, ENST00000685232, ENST00000688307, ENST00000688574, ENST00000688903, ENST00000690892, ENST00000691124, ENST00000714260, ENST00000714261, ENST00000714262, ENST00000714263, ENST00000714264, ENST00000714265, ENST00000714266, ENST00000714267, ENST00000714268, ENST00000714269, ENST00000714270, ENST00000714271, ENST00000714272, ENST00000714273, ENST00000714274, ENST00000877432, ENST00000877433, ENST00000932317, ENST00000932318, ENST00000932319, ENST00000971068, ENST00000971069, ENST00000971070, ENST00000971071, ENST00000971072

RefSeq mRNA: 4 — MANE Select: NM_005359 NM_001407041, NM_001407042, NM_001407043, NM_005359

CCDS: CCDS11950

Canonical transcript exons

ENST00000342988 — 12 exons

Exon	Start	End
ENSE00002877760	51048686	51048860
ENSE00003669145	51046920	51047295
ENSE00004013727	51059866	51059916
ENSE00004013728	51067019	51067187
ENSE00004013729	51054781	51054993
ENSE00004013730	51076638	51076776
ENSE00004013731	51065423	51065606
ENSE00004013733	51078256	51085042
ENSE00004013734	51049295	51049324
ENSE00004013735	51058340	51058456
ENSE00004013736	51058125	51058244
ENSE00004023391	51030213	51030623

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.7144 / max 432.6813, expressed in 1816 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170269	58.7144	1816

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.52	gold quality
ganglionic eminence	UBERON:0004023	97.77	gold quality
calcaneal tendon	UBERON:0003701	97.63	gold quality
adrenal tissue	UBERON:0018303	96.97	gold quality
colonic epithelium	UBERON:0000397	96.66	gold quality
stromal cell of endometrium	CL:0002255	96.05	gold quality
tendon	UBERON:0000043	95.93	gold quality
cortical plate	UBERON:0005343	95.88	gold quality
left ovary	UBERON:0002119	95.79	gold quality
gall bladder	UBERON:0002110	95.77	gold quality
rectum	UBERON:0001052	95.74	gold quality
popliteal artery	UBERON:0002250	95.65	gold quality
tibial artery	UBERON:0007610	95.63	gold quality
embryo	UBERON:0000922	95.54	gold quality
body of uterus	UBERON:0009853	95.38	gold quality
endocervix	UBERON:0000458	95.35	gold quality
islet of Langerhans	UBERON:0000006	95.31	gold quality
descending thoracic aorta	UBERON:0002345	95.23	gold quality
right ovary	UBERON:0002118	95.18	gold quality
mucosa of stomach	UBERON:0001199	94.97	gold quality
aorta	UBERON:0000947	94.95	gold quality
left lobe of thyroid gland	UBERON:0001120	94.90	gold quality
right lobe of thyroid gland	UBERON:0001119	94.88	gold quality
parietal pleura	UBERON:0002400	94.86	gold quality
right coronary artery	UBERON:0001625	94.83	gold quality
thyroid gland	UBERON:0002046	94.79	gold quality
endometrium	UBERON:0001295	94.78	gold quality
ovary	UBERON:0000992	94.70	gold quality
gastrocnemius	UBERON:0001388	94.66	gold quality
muscle of leg	UBERON:0001383	94.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.30
E-MTAB-6142	no	38.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

157 targets.

Target	Regulation
ADAM2
AGR2
AGTR1	Unknown
AHR	Unknown
ALPI	Activation
ANKRD1	Activation
APOC3	Activation
APP	Unknown
AR	Repression
ATOH8	Activation
BAMBI	Activation
BAX	Unknown
BBC3	Activation
BCL2	Unknown
BCL2L11	Activation
BGLAP	Unknown
BMP4	Activation
BMP6	Repression
BTRC	Repression
CAT
CCL15	Unknown
CCL2	Activation
CCL20	Activation
CCN1	Activation
CCN2	Unknown
CCND1	Unknown
CCNG2	Activation
CD79A	Unknown
CDH1	Unknown
CDH2	Activation

Upstream regulators (CollecTRI, top): ETS1, FOS, FOXO1, FOXO3, GLI1, HDAC4, HIF1A, JUNB, KAT2B, KLF10, OVOL2, SMAD2, SP1, TGFB2, ZNF451

miRNA regulators (miRDB)

361 targeting SMAD4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• DNA-binding protein (PMID:10871368)
• Alterations in tumor-suppressor gene DPC4 may play an important role during the tumorigenesis of pancreatic cancer. (PMID:11783110)
• A point mutation in Smad4 abolished binding to SMIF. (PMID:11836524)
• smad4 may play an important role in the regulation of TGFbeta inducible gene expression and subsequent growth inhibition. (PMID:11866987)
• Common deletion of SMAD4 in juvenile polyposis is a mutational hotspot. (PMID:11920286)
• TLV-1 tax represses Smad-mediated TGF-beta signaling. (PMID:12097320)
• Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. (PMID:12191474)
• In this study, the expression of Smad4 protein appeared to be correlated with the depth of invasion of esophageal SCC (PMID:12209716)
• interactions between AR, Smad3, and Smad4 may result in the differential regulation of the AR transactivation, which further strengthens their roles in the prostate cancer progression (PMID:12226080)
• Restoration of transforming growth factor Beta signaling by functional expression of smad4 induces anoikis. (PMID:12414627)
• determined the crystal structure of a complex between a conserved Smad4 binding fragment of Ski and the MH2 domain of Smad4 at 2.85 A resolution (PMID:12419246)
• Smad4/DPC4 has a role in TGF-beta-mediated inhibition of cell proliferation in vitro and in vivo (PMID:12429655)
• Phenotypic and functional changes associated with TGF-beta1-induced fibroblast terminal differentiation are differentially regulated by Smad2, Smad3, and Smad4. (PMID:12531695)
• the re-expression of the Smad4 gene by either method partially restored TGF-beta responsiveness in FaDu cells with respect to both growth inhibition and expression of p21WAF1/CIP1 and p15INK4B (PMID:12548549)
• Smad4 point mutations are prevalent in pancreatic carcinoma, they are infrequent in early stages (I-III) of colorectal cancer. (PMID:12569386)
• Interaction domains of Smad4 and ERalpha are mapped and shown to be essential for transcriptional repression of ERalpha by Smad4. (PMID:12576474)
• Smad4 is not required for nuclear translocation of Smad2 and Smad3, but is needed for activation of at least certain transcriptional responses. (PMID:12618756)
• Results suggest that the transcriptional cross talk between the TGFbeta-regulated Smads 3 and 4 and hepatocyte nuclear factor-4 is mediated by specific functional domains in the two types of transcription factors. (PMID:12631740)
• Human HCC transfectants express a mutant Smad2(3S-A). Serine residues of SSXS motif were changed to alanine. They have impaired Smad2 signaling. Forced expression of Smad2(3S-A induced TGFB secretion & resistance to TGFB-induced growth inhibition. (PMID:12700666)
• results suggest carcinogenesis in the biliary tract epithelium in anomalous pancreaticobiliary ductal union (APBDU) is accompanied by multistep mutational events; inactivation of DPC-4 gene accumulates late in progression of biliary tract adenocarcinoma (PMID:12720172)
• Smad4 is sumoylated and has a role in the regulation of TGF-beta signaling through Smads (PMID:12740389)
• Smad-4 had no effect on the basal activity of the MCP-1 promoter, but showed the ability to decrease both Smad-3 and Tat-induced transcription of the MCP promoter in human astrocytic cells (PMID:12758167)
• oligo-ubiquitination positively regulates Smad4 function, whereas poly-ubiquitination primarily occurs in unstable cancer mutants and leads to protein degradation (PMID:12794086)
• duration of TGF-beta-Smad signaling is a critical determinant of the specificity of the TGF-beta response. (PMID:12802277)
• SUMO-1 modification serves to protect Smad4 from ubiquitin-dependent degradation and consequently enhances the growth inhibitory and transcriptional responses of Smad4. (PMID:12813045)
• A G/A transition at 31 bp upstream-nontranslated regions of exon 8 of Smad 4 was found in cervical cancer cells, highlighting an important role for Smad 4 in human cervical tumors. (PMID:12894231)
• Smad4 interaction with CAN/Nup214, and nuclear import requires structural elements present only in the full-length Smad4; Smad3 and Smad4 have different susceptibility to inhibition of import by cytoplasmic retention factor SARA (PMID:12917407)
• Smad4 was expressed in all thyroid cell lines and controls analyzed, differently from other classes of tumors where Smad4 expression was deleted. (PMID:12952364)
• Sumoylation of Smad4 mainly occurs at lysine 159 and facilitates Smad-dependent transcriptional activation; PIAS-mediated sumoylation of Smad4 is regulated by the p38 MAP kinase pathway (PMID:14514699)
• DACH1 bound to endogenous NCoR and Smad4 in cultured cells; Smad4 was required for DACH1 repression of TGF-beta induction of Smad signaling (PMID:14525983)
• Smad2, Smad3 and Smad4 contribute to the regulation of TGF-beta responses to varying extents, and exhibit distinct roles in different cell types (PMID:14555988)
• Inactivation of DPC4 gene late in neoplastic progression of pancreatic carcinoma. Variation of DPC4 gene activation in biliary tract carcinoma. Common bile duct carcinoma and pancreatic carcinoma have similar molecular alternations. (PMID:14607700)
• SMAD3 and SMAD4 activate gadd45beta through its third intron to facilitate G2 progression following TGFbeta treatment (PMID:14630914)
• DPC4/Smad4 inactivation by mutation or deletion appears to be very rare in pancreatic endocrine tumors. (PMID:14639103)
• Mutations in SMAD4 abrogate its function in transducing the signaling of TGF-beta, which plays an important role in various stages of cancer formation. (PMID:14647410)
• DPC4 mutations in appendiceal adenocarcinomas suggests involvement of DPC4 and nearby genes on chromosome 18q (DCC and/or JV-18) in the pathogenesis of appendiceal adenocarcinomas (PMID:14647445)
• DPC4 is involved in the development of pancreatic carcinoma and is a late event in pancreatic carcinogenesis. (PMID:14669329)
• DLX1 is expressed in hematopoietic cells in a lineage-dependent manner and that DLX1 interacts with Smad4 through its homeodomain (PMID:14671321)
• CHIP can interact with the Smad1/Smad4 proteins and block BMP signal transduction through the ubiquitin-mediated degradation of Smad proteins. (PMID:14701756)
• Two missense mutations in the C-terminal domain of Smad4, D351H (Asp351–>His) & D537Y (Asp537–>Tyr), from colorectal cancer cells cannot interact with either TGF-beta-induced phosphorylated Smad2 or Smad3. (PMID:14715079)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	smad4b	ENSDARG00000012649
danio_rerio	smad4a	ENSDARG00000075226
mus_musculus	Smad4	ENSMUSG00000024515
rattus_norvegicus	Smad4	ENSRNOG00000051965
drosophila_melanogaster	Dad	FBGN0020493
caenorhabditis_elegans		WBGENE00000910
caenorhabditis_elegans	tag-68	WBGENE00006445

Paralogs (7): SMAD7 (ENSG00000101665), SMAD5 (ENSG00000113658), SMAD9 (ENSG00000120693), SMAD6 (ENSG00000137834), SMAD3 (ENSG00000166949), SMAD1 (ENSG00000170365), SMAD2 (ENSG00000175387)

Protein

Protein identifiers

SMAD family member 4 — Q13485 (reviewed: Q13485)

Alternative names: Deletion target in pancreatic carcinoma 4, Mothers against decapentaplegic homolog 4

All UniProt accessions (25): A0A024R274, A0A087WUF3, A0AAQ5BHQ0, A0AAQ5BHQ2, A0AAQ5BHS5, A0AAQ5BHS9, A0AAQ5BHT7, A0AAQ5BHU0, Q13485, A0AAQ5BHU1, A0AAQ5BHU2, A0AAQ5BHU9, A0AAQ5BHV1, A0AAQ5BHV2, A0AAQ5BHV5, A0AAQ5BHW2, A0AAQ5BHY6, A0AAQ5BHZ6, K7EIJ2, K7EIU8, K7EL15, K7EL18, K7ELK2, K7ENG1, K7ES96

UniProt curated annotations — full annotation on UniProt →

Function. In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5’-GTCT/AGAC-3’) within BMP response element (BMPRE) of cardiac activating regions. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.

Subunit / interactions. Monomer; in the absence of TGF-beta activation. Heterotrimer; on TGF-beta activation. Heterotrimer composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found in a complex with SMAD1 and YY1. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains). Interacts with ZC3H3. Interacts weakly with ZNF8. Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling. Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as a CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix. Interacts with DLX1. Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1. Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A. Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A. Interacts with HDAC1. Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex. Interacts (via N-terminus) with TSC22D1.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated by PDPK1. Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.

Disease relevance. Pancreatic cancer (PNCA) [MIM:260350] A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. The gene represented in this entry may be involved in disease pathogenesis. Juvenile polyposis syndrome (JPS) [MIM:174900] Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. The disease is caused by variants affecting the gene represented in this entry. Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050] JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown. The disease is caused by variants affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The disease may be caused by variants affecting the gene represented in this entry. SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a 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. Myhre syndrome (MYHRS) [MIM:139210] An autosomal dominant syndrome characterized by pre- and postnatal growth deficiency, intellectual disability, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MH1 domain is required for DNA binding. The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.

Similarity. Belongs to the dwarfin/SMAD family.

RefSeq proteins (4): NP_001393970, NP_001393971, NP_001393972, NP_005350* (*=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 (78 total): strand 21, helix 15, sequence variant 12, region of interest 5, mutagenesis site 5, turn 5, binding site 4, modified residue 3, domain 2, cross-link 2, compositionally biased region 2, chain 1, site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6YIC	X-RAY DIFFRACTION	1.6
5MEY	X-RAY DIFFRACTION	2.05
1YGS	X-RAY DIFFRACTION	2.1
5UWU	X-RAY DIFFRACTION	2.24
1U7F	X-RAY DIFFRACTION	2.6
5C4V	X-RAY DIFFRACTION	2.6
1DD1	X-RAY DIFFRACTION	2.62
1U7V	X-RAY DIFFRACTION	2.7
1MR1	X-RAY DIFFRACTION	2.85
5MEZ	X-RAY DIFFRACTION	2.98
1G88	X-RAY DIFFRACTION	3
5MF0	X-RAY DIFFRACTION	3.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13485-F1	74.56	0.53

Functional residue map

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

Catalytic / active sites (1): 515 (necessary for heterotrimerization)

Ligand- & substrate-binding residues (4): 71; 115; 127; 132

Post-translational modifications (5): 37, 428, 507, 113, 519

Mutagenesis-validated functional residues (5):

Position	Phenotype
416	no effect on heterotrimerization. partially diminished transcriptional activation.
496	no effect on heterotrimerization. partially diminished transcriptional activation.
502	no effect on heterotrimerization. greatly reduced transcriptional activation.
515	reduced heterotrimerization.
519	abolishes ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

49 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1502540	Signaling by Activin
R-HSA-201451	Signaling by BMP
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-3311021	SMAD4 MH2 Domain Mutants in Cancer
R-HSA-3315487	SMAD2/3 MH2 Domain Mutants in Cancer
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8941326	RUNX2 regulates bone development
R-HSA-8941855	RUNX3 regulates CDKN1A transcription
R-HSA-8952158	RUNX3 regulates BCL2L11 (BIM) transcription
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9733709	Cardiogenesis
R-HSA-9735871	SARS-CoV-1 targets host intracellular signalling and regulatory pathways
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9823730	Formation of definitive endoderm
R-HSA-9839394	TGFBR3 expression
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-3304347	Loss of Function of SMAD4 in Cancer
R-HSA-3304349	Loss of Function of SMAD2/3 in Cancer
R-HSA-3304351	Signaling by TGF-beta Receptor Complex in Cancer

MSigDB gene sets: 1136 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_SINGLE_FERTILIZATION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GRUETZMANN_PANCREATIC_CANCER_DN

GO Biological Process (95): negative regulation of transcription by RNA polymerase II (GO:0000122), ovarian follicle development (GO:0001541), osteoblast differentiation (GO:0001649), branching involved in ureteric bud morphogenesis (GO:0001658), response to hypoxia (GO:0001666), in utero embryonic development (GO:0001701), gastrulation with mouth forming second (GO:0001702), epithelial to mesenchymal transition (GO:0001837), outflow tract septum morphogenesis (GO:0003148), cardiac conduction system development (GO:0003161), atrioventricular valve formation (GO:0003190), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), left ventricular cardiac muscle tissue morphogenesis (GO:0003220), obsolete positive regulation of cell proliferation involved in heart valve morphogenesis (GO:0003251), brainstem development (GO:0003360), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), intracellular iron ion homeostasis (GO:0006879), transforming growth factor beta receptor signaling pathway (GO:0007179), spermatogenesis (GO:0007283), single fertilization (GO:0007338), axon guidance (GO:0007411), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), anatomical structure morphogenesis (GO:0009653), negative regulation of cardiac muscle hypertrophy (GO:0010614), positive regulation of gene expression (GO:0010628), epithelial cell migration (GO:0010631), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), positive regulation of epithelial to mesenchymal transition (GO:0010718), neural crest cell differentiation (GO:0014033), cardiac muscle hypertrophy in response to stress (GO:0014898), cell differentiation (GO:0030154), negative regulation of cell growth (GO:0030308), adrenal gland development (GO:0030325), BMP signaling pathway (GO:0030509), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), somite rostral/caudal axis specification (GO:0032525)

GO Molecular Function (23): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription corepressor binding (GO:0001222), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), collagen binding (GO:0005518), filamin binding (GO:0031005), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), sulfate binding (GO:0043199), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), I-SMAD binding (GO:0070411), R-SMAD binding (GO:0070412), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515), protein-containing complex binding (GO:0044877), SMAD binding (GO:0046332)

GO Cellular Component (14): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), activin responsive factor complex (GO:0032444), ciliary basal body (GO:0036064), SMAD protein complex (GO:0071141), heteromeric SMAD protein complex (GO:0071144), ciliary tip (GO:0097542), protein-containing complex (GO:0032991), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Developmental Biology	3
Signaling by TGFB family members	2
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
Transcriptional regulation by RUNX3	2
FOXO-mediated transcription	2
Gastrulation	2
Signaling by TGF-beta Receptor Complex	1
Loss of Function of SMAD4 in Cancer	1
Loss of Function of SMAD2/3 in Cancer	1
Deubiquitination	1
Transcriptional regulation by RUNX2	1
SARS-CoV-1-host interactions	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
anatomical structure development	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
transcription coregulator binding	2
transcription cis-regulatory region binding	2
SMAD binding	2
protein-containing complex	2
microtubule organizing center	2
RNA polymerase II transcription regulator complex	2
cilium	2
negative regulation of DNA-templated transcription	1
female gonad development	1
ossification	1
cell differentiation	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
chordate embryonic development	1
gastrulation	1
mesenchymal cell differentiation	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
cardiac muscle tissue development	1
atrioventricular valve morphogenesis	1
heart valve formation	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
cardiac left ventricle morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1

Protein interactions and networks

STRING

4822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAD4	CTNNB1	P35222	994
SMAD4	SMAD2	Q15796	990
SMAD4	FOXH1	O75593	990
SMAD4	SKIL	P12756	990
SMAD4	LEF1	Q9UJU2	989
SMAD4	SMAD3	P84022	989
SMAD4	SMAD9	O15198	988
SMAD4	JUN	P05412	988
SMAD4	SMAD5	Q99717	988
SMAD4	HNF4A	P41235	987
SMAD4	TGFBR1	P36897	975
SMAD4	E2F4	Q16254	972
SMAD4	TGFBR2	P37173	961
SMAD4	SMAD6	O43541	958
SMAD4	SNAI1	O95863	957

IntAct

1627 interactions, top by confidence:

A	B	Type	Score
SMAD3	SMAD4	psi-mi:“MI:0407”(direct interaction)	0.980
SMAD3	SMAD4	psi-mi:“MI:0915”(physical association)	0.980
SMAD3	SMAD4	psi-mi:“MI:2364”(proximity)	0.980
SMAD4	SMAD3	psi-mi:“MI:0915”(physical association)	0.980
SMAD3	SMAD4	psi-mi:“MI:0914”(association)	0.980
SMAD4	SMAD2	psi-mi:“MI:0407”(direct interaction)	0.970
SMAD4	SMAD2	psi-mi:“MI:0915”(physical association)	0.970
SMAD2	SMAD4	psi-mi:“MI:0915”(physical association)	0.970

BioGRID (871): LMO4 (Two-hybrid), RASSF5 (Two-hybrid), SMAD4 (Affinity Capture-Western), SMAD4 (Reconstituted Complex), SMAD4 (Protein-peptide), BTRC (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SMAD4 (Reconstituted Complex), Dok1 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SMAD2 (Affinity Capture-Western), SMAD3 (Affinity Capture-Western), Rhog (Affinity Capture-Luminescence)

ESM2 similar proteins: A3LQ10, F4IXJ7, F5GUE5, F5HFZ4, O70437, O94262, P0C734, P0CA74, P14162, P16794, P25046, P30119, P33246, P34619, P38782, P39995, P45897, P69481, P69482, P69483, P97471, Q03564, Q03782, Q04572, Q09585, Q13485, Q14938, Q16RI1, Q19863, Q1HE26, Q26231, Q2LZ58, Q499Y3, Q5A2Z1, Q5H9N3, Q5UQL4, Q65185, Q6BIH7, Q6CTT6, Q6CWB2

Diamond homologs: O15198, O35182, O54835, O70436, O70437, P42003, P45896, P45897, P70340, P84022, P84023, P84024, P84025, P97454, P97471, P97588, Q02330, Q13485, Q15796, Q15797, Q1HE26, Q1JQA2, Q1W668, Q21733, Q56I99, Q5R6H7, Q5R7C0, Q62432, Q8BUN5, Q95QI7, Q99717, Q9GKQ9, Q9I8V2, Q9I962, Q9I9P9, Q9JIW5, Q9R1V3, Q9W7E7, O15105, O35253

SIGNOR signaling

51 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	SMAD4	phosphorylation
MAPK3	up-regulates	SMAD4	phosphorylation
SMAD4	“form complex”	SMAD1/4	binding
PIAS4	down-regulates	SMAD4	binding
COPS5	down-regulates	SMAD4	ubiquitination
NUP214	up-regulates	SMAD4	binding
BTRC	down-regulates	SMAD4	ubiquitination
FBXW11	up-regulates	SMAD4	ubiquitination
PIAS1	up-regulates	SMAD4	sumoylation
SKP2	down-regulates	SMAD4	ubiquitination
SMAD1	up-regulates	SMAD4	phosphorylation
SMAD5	up-regulates	SMAD4	phosphorylation
SMAD9	up-regulates	SMAD4	phosphorylation
SMAD1	up-regulates	SMAD4	binding
USP9X	up-regulates	SMAD4	deubiquitination
SMAD6	“down-regulates activity”	SMAD4	binding
AMOT/MPP5/INADL/LIN7C	up-regulates	SMAD4	binding
SMAD4	“up-regulates activity”	LEF1
SMAD4	“form complex”	SMAD3/SMAD4	binding
SMAD3	“up-regulates activity”	SMAD4	binding
SMAD4	“form complex”	SMAD2/SMAD4	binding
SMAD2	“up-regulates activity”	SMAD4	binding
SKI	“down-regulates activity”	SMAD4	binding
SMURF1	“down-regulates activity”	SMAD4	ubiquitination
SKIL	“down-regulates activity”	SMAD4	binding
ERK1/2	up-regulates	SMAD4	phosphorylation
SMAD4	“down-regulates quantity by repression”	MYC	“transcriptional regulation”
SMURF	“down-regulates activity”	SMAD4	ubiquitination
SMAD4	“form complex”	SMAD5/SMAD4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
FOXO-mediated transcription of cell cycle genes	5	63.4×	1e-06
Downregulation of SMAD2/3:SMAD4 transcriptional activity	6	41.7×	1e-06
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	5	35.9×	2e-05
Chemokine receptors bind chemokines	7	24.7×	1e-06
Deubiquitination	6	14.1×	3e-04
Signaling by TGFB family members	6	13.1×	3e-04
Interleukin-4 and Interleukin-13 signaling	6	11.7×	3e-04
Ub-specific processing proteases	8	8.0×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
SMAD protein signal transduction	6	70.9×	4e-08
eosinophil chemotaxis	5	59.1×	2e-06
chemokine-mediated signaling pathway	7	36.6×	1e-07
positive regulation of miRNA transcription	5	23.4×	1e-04
humoral immune response	5	22.6×	1e-04
antimicrobial humoral immune response mediated by antimicrobial peptide	8	20.9×	6e-07
transforming growth factor beta receptor signaling pathway	8	20.5×	6e-07
cellular response to virus	6	19.4×	4e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 18 cancer types — BRCA, CESC, CHOL, COAD, COADREAD, ESCA, ESCC, GBC, HNSC, LUAD, NSCLC, PAAD…(+6 more).

Clinical variants and AI predictions

ClinVar

2620 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	240
Likely pathogenic	55
Uncertain significance	1123
Likely benign	558
Benign	103

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1050635	NM_005359.6(SMAD4):c.733C>T (p.Gln245Ter)	Pathogenic
1070021	NC_000018.9:g.(?48604616)(48604837_?)del	Pathogenic
1070022	NC_000018.9:g.(?48593383)(48604842_?)del	Pathogenic
1073157	NM_005359.6(SMAD4):c.620del (p.Asn207fs)	Pathogenic
1074223	NM_005359.6(SMAD4):c.779dup (p.Tyr260Ter)	Pathogenic
1074875	NM_005359.6(SMAD4):c.223del (p.Gln75fs)	Pathogenic
1075033	NM_005359.6(SMAD4):c.1494dup (p.Cys499fs)	Pathogenic
1076671	NM_005359.6(SMAD4):c.968G>A (p.Trp323Ter)	Pathogenic
1076948	NM_005359.6(SMAD4):c.563del (p.Asn188fs)	Pathogenic
1351575	NM_005359.6(SMAD4):c.23del (p.Asn8fs)	Pathogenic
1363053	NM_005359.6(SMAD4):c.1125_1128dup (p.Glu377delinsHisTer)	Pathogenic
1380059	NM_005359.6(SMAD4):c.713_719del (p.Leu237_Leu238insTer)	Pathogenic
1390653	NM_005359.6(SMAD4):c.112del (p.Arg38fs)	Pathogenic
1392952	NM_005359.6(SMAD4):c.237_241dup (p.Arg81fs)	Pathogenic
1395560	NM_005359.6(SMAD4):c.348_349del (p.Tyr117fs)	Pathogenic
1402744	NM_005359.6(SMAD4):c.714dup (p.Gln239fs)	Pathogenic
140903	NM_005359.6(SMAD4):c.1345C>T (p.Gln449Ter)	Pathogenic
1409550	NM_005359.6(SMAD4):c.332_333del (p.His111fs)	Pathogenic
1417860	NM_005359.6(SMAD4):c.1373dup (p.Ala459fs)	Pathogenic
1419311	NM_005359.6(SMAD4):c.742C>T (p.Gln248Ter)	Pathogenic
142253	NM_005359.6(SMAD4):c.1245_1248del (p.Asp415Glufs)	Pathogenic
1434302	NM_005359.6(SMAD4):c.472del (p.Met157_Val158insTer)	Pathogenic
1442723	NM_005359.6(SMAD4):c.296G>A (p.Trp99Ter)	Pathogenic
1448680	NM_005359.6(SMAD4):c.1017dup (p.Lys340Ter)	Pathogenic
1453585	NM_005359.6(SMAD4):c.1548del (p.Ser517fs)	Pathogenic
1453882	NM_005359.6(SMAD4):c.1415dup (p.Gly473fs)	Pathogenic
1456071	NC_000018.9:g.(?48591783)(48591986_?)del	Pathogenic
1457361	NM_005359.6(SMAD4):c.902dup (p.Tyr301Ter)	Pathogenic
1458397	NM_005359.6(SMAD4):c.1176dup (p.Gly393fs)	Pathogenic
1459423	NC_000018.9:g.(?48602998)(48604837_?)del	Pathogenic

SpliceAI

2425 predictions. Top by Δscore:

Variant	Effect	Δscore
18:51048676:A:AG	acceptor_gain	1.0000
18:51048681:TCTA:T	acceptor_loss	1.0000
18:51048682:CTA:C	acceptor_loss	1.0000
18:51048683:TAGGT:T	acceptor_loss	1.0000
18:51048684:A:AG	acceptor_gain	1.0000
18:51048684:AG:A	acceptor_gain	1.0000
18:51048684:AGGT:A	acceptor_gain	1.0000
18:51048684:AGGTG:A	acceptor_gain	1.0000
18:51048685:G:GG	acceptor_gain	1.0000
18:51048685:GG:G	acceptor_gain	1.0000
18:51048685:GGT:G	acceptor_gain	1.0000
18:51048685:GGTG:G	acceptor_gain	1.0000
18:51048685:GGTGG:G	acceptor_gain	1.0000
18:51048857:ATTGG:A	donor_loss	1.0000
18:51048858:TTG:T	donor_gain	1.0000
18:51048859:TG:T	donor_gain	1.0000
18:51048860:GG:G	donor_gain	1.0000
18:51048860:GGT:G	donor_loss	1.0000
18:51048860:GGTA:G	donor_loss	1.0000
18:51048861:G:GG	donor_gain	1.0000
18:51048861:GTAA:G	donor_loss	1.0000
18:51048862:TAA:T	donor_loss	1.0000
18:51054776:T:G	acceptor_gain	1.0000
18:51054776:TATA:T	acceptor_loss	1.0000
18:51054777:A:AG	acceptor_gain	1.0000
18:51054778:T:G	acceptor_gain	1.0000
18:51054779:A:AC	acceptor_loss	1.0000
18:51054779:A:AG	acceptor_gain	1.0000
18:51054780:G:GT	acceptor_gain	1.0000
18:51054780:GC:G	acceptor_gain	1.0000

AlphaMissense

3631 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:51047086:G:C	D14H	1.000
18:51047090:C:A	A15D	1.000
18:51047092:T:C	C16R	1.000
18:51047094:T:G	C16W	1.000
18:51047098:A:C	S18R	1.000
18:51047100:C:A	S18R	1.000
18:51047100:C:G	S18R	1.000
18:51047102:T:A	I19N	1.000
18:51047102:T:G	I19S	1.000
18:51047107:C:G	H21D	1.000
18:51047110:A:C	S22R	1.000
18:51047112:T:A	S22R	1.000
18:51047112:T:G	S22R	1.000
18:51047114:T:C	L23S	1.000
18:51047114:T:G	L23W	1.000
18:51047119:T:C	C25R	1.000
18:51047122:C:G	H26D	1.000
18:51047149:T:C	F35L	1.000
18:51047150:T:C	F35S	1.000
18:51047150:T:G	F35C	1.000
18:51047151:T:A	F35L	1.000
18:51047151:T:G	F35L	1.000
18:51047160:A:C	R38S	1.000
18:51047160:A:T	R38S	1.000
18:51047161:G:C	A39P	1.000
18:51047162:C:A	A39E	1.000
18:51047165:T:A	I40N	1.000
18:51047167:G:A	E41K	1.000
18:51047170:A:C	S42R	1.000
18:51047172:T:A	S42R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001497 (18:51082542 AG>A), RS1000141519 (18:51057357 A>G,T), RS1000154868 (18:51072462 C>T), RS1000183737 (18:51075724 A>G), RS1000187778 (18:51070397 T>C), RS1000233606 (18:51072802 A>T), RS1000246941 (18:51043710 G>A), RS1000257327 (18:51075325 A>G), RS1000278095 (18:51043528 A>G), RS1000302096 (18:51032844 T>A), RS1000352096 (18:51038415 G>A), RS1000404705 (18:51038253 G>A,C,T), RS1000511827 (18:51057654 C>G), RS1000615329 (18:51083907 G>A), RS1000652445 (18:51033134 A>T)

Disease associations

OMIM: gene MIM:600993 | disease phenotypes: MIM:174900, MIM:607086, MIM:139210, MIM:175050, MIM:260350, MIM:613659, MIM:187300, MIM:233100, MIM:211980, MIM:178600, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Definitive	Autosomal dominant
Myhre syndrome	Definitive	Autosomal dominant
generalized juvenile polyposis/juvenile polyposis coli	Strong	Autosomal dominant
juvenile polyposis syndrome	Strong	Autosomal dominant
hereditary hemorrhagic telangiectasia	Supportive	Autosomal dominant
familial thoracic aortic aneurysm and aortic dissection	Supportive	Autosomal dominant
pulmonary arterial hypertension	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
pulmonary arterial hypertension	Disputed	AD
Myhre syndrome	Definitive	AD
juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Definitive	AD

Mondo (23): hereditary neoplastic syndrome (MONDO:0015356), juvenile polyposis syndrome (MONDO:0017380), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), exocrine pancreatic carcinoma (MONDO:0005192), Myhre syndrome (MONDO:0007688), juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MONDO:0008278), generalized juvenile polyposis/juvenile polyposis coli (MONDO:0008276), breast cancer (MONDO:0007254), colon carcinoma (MONDO:0002032), familial pancreatic carcinoma (MONDO:0015278), gastric cancer (MONDO:0001056), pulmonary arterial hypertension (MONDO:0015924), hereditary hemorrhagic telangiectasia (MONDO:0019180), Wilms tumor (MONDO:0006058), gallbladder cancer (MONDO:0005411)

Orphanet (15): Inherited cancer-predisposing syndrome (Orphanet:140162), Juvenile polyposis syndrome (Orphanet:2929), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Familial pancreatic carcinoma (Orphanet:1333), Rare carcinoma of pancreas (Orphanet:217074), Myhre syndrome (Orphanet:2588), Generalized juvenile polyposis/juvenile polyposis coli (Orphanet:329971), Pulmonary arterial hypertension (Orphanet:182090), Hereditary hemorrhagic telangiectasia (Orphanet:774), Nephroblastoma (Orphanet:654), Familial renal glucosuria (Orphanet:69076), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Moyamoya angiopathy (Orphanet:477768), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

242 total (30 of 242 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000036	Abnormal penis morphology
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000098	Tall stature
HP:0000135	Hypogonadism
HP:0000159	Abnormal lip morphology
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000214	Lip telangiectasia
HP:0000219	Thin upper lip vermilion
HP:0000220	Velopharyngeal insufficiency
HP:0000227	Tongue telangiectasia
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000421	Epistaxis

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001547_5	Immune response to anthrax vaccine	1.000000e-06
GCST002758_2	Oligoclonal band status in multiple sclerosis	8.000000e-07
GCST007797_43	Asthma onset (childhood vs adult)	5.000000e-06
GCST007798_121	Asthma	6.000000e-08
GCST007800_99	Asthma (childhood onset)	4.000000e-13
GCST009391_140	Metabolite levels	5.000000e-06
GCST010043_39	Asthma	2.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0005206	oligoclonal band measurement
EFO:0004847	age at onset
EFO:0010475	deoxycholate measurement

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D006030	Glycosuria, Renal	C12.050.351.968.419.815.532; C12.050.351.968.934.363.450; C12.200.777.419.815.532; C12.200.777.934.363.450; C12.950.419.815.532; C12.950.934.363.450; C16.320.831.532; C18.452.394.937.450
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D013683	Telangiectasia, Hereditary Hemorrhagic	C14.907.454.900; C14.907.823.780; C15.378.463.515.900; C16.131.240.850.968
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
C537620	Growth mental deficiency syndrome of Myhre (supp.)
C563412	Juvenile Polyposis with Hereditary Hemorrhagic Telangiectasia (supp.)
C535837	Pancreatic carcinoma, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725109 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items; also 9 prognostic, 2 functional, 1 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
SMAD4 Underexpression	Gemcitabine	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID6437
SMAD4 Deletion	Fluorouracil	Colorectal Cancer	Resistance	CIViC B	EID1644
SMAD4 Mutation	Panitumumab + Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID719
SMAD4 Underexpression	Cetuximab	Head And Neck Squamous Cell Carcinoma	Resistance	CIViC D	EID720

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	8
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Resveratrol	decreases expression	3
Doxorubicin	affects cotreatment, decreases reaction, increases expression, decreases expression	3
methylmercuric chloride	decreases expression	2
bisphenol A	decreases expression	2
trichostatin A	affects cotreatment, increases expression	2
Ethanol	decreases expression, decreases reaction, increases expression	2
Arsenic	decreases expression, increases abundance, affects methylation, affects cotreatment	2
Cadmium	decreases expression, decreases reaction, increases abundance, affects expression	2
Carbamazepine	affects expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases reaction, increases expression, decreases expression	2
Cyclosporine	decreases reaction, increases expression	2
Doxazosin	increases reaction, increases expression	2
vericiguat	decreases reaction, increases expression	1
bisphenol F	increases expression	1
moringin	decreases expression, increases expression	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
methotrexate polyglutamate	affects abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
vanadyl sulfate	decreases expression	1
galangin	increases expression, decreases reaction	1
osthol	affects cotreatment, decreases expression	1
evodiamine	decreases reaction, affects localization	1
tamibarotene	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697302	Binding	Inhibition of SMAD4 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

355 cell lines: 346 cancer cell line, 4 transformed cell line, 3 embryonic stem cell, 1 finite cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0025	Caco-2	Cancer cell line	Male
CVCL_0144	ARO	Cancer cell line	Female
CVCL_0152	AsPC-1	Cancer cell line	Female
CVCL_0186	BxPC-3	Cancer cell line	Female
CVCL_0232	Caco-2/15	Cancer cell line	Male
CVCL_0233	Caco-2/TC-7	Cancer cell line	Male
CVCL_0237	Capan-1	Cancer cell line	Male
CVCL_0320	HT-29	Cancer cell line	Female
CVCL_0322	HT29 gluc C1	Cancer cell line	Female
CVCL_0323	HT29-19A	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial