CRIPTO

Summary

CRIPTO (cripto, EGF-CFC family member, HGNC:11701) is a protein-coding gene on chromosome 3p21.31, encoding Protein Cripto (P13385). GPI-anchored cell membrane protein involved in Nodal signaling. It is a selective cancer dependency (DepMap: 57.5% of cell lines).

This gene encodes an epidermal growth factor-related protein that contains a cripto, FRL-1, and cryptic domain. The encoded protein is an extracellular, membrane-bound signaling protein that plays an essential role in embryonic development and tumor growth. Mutations in this gene are associated with forebrain defects. Pseudogenes of this gene are found on chromosomes 2, 3, 6, 8, 19 and X. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 6997 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 68 total
• Phenotypes (HPO): 115
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 57.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11701
Approved symbol	CRIPTO
Name	cripto, EGF-CFC family member
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	CR, Cripto-1, CR-1
Ensembl gene	ENSG00000241186
Ensembl biotype	protein_coding
OMIM	187395
Entrez	6997

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 3 retained_intron

ENST00000296145, ENST00000459867, ENST00000471721, ENST00000493282, ENST00000542931, ENST00000863382, ENST00000938305, ENST00000938306, ENST00000938307, ENST00000938308, ENST00000938309, ENST00000938310, ENST00000938311, ENST00000938312, ENST00000938313, ENST00000938314, ENST00000951684

RefSeq mRNA: 2 — MANE Select: NM_003212 NM_001174136, NM_003212

CCDS: CCDS2742, CCDS54575

Canonical transcript exons

ENST00000296145 — 6 exons

Exon	Start	End
ENSE00001078649	46579739	46579853
ENSE00001078650	46579951	46580060
ENSE00001423089	46581132	46582457
ENSE00001942602	46577788	46578004
ENSE00003517910	46579232	46579366
ENSE00003579118	46579095	46579147

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 87.73.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9725 / max 89.8936, expressed in 102 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36492	0.4081	83
36490	0.3437	53
36489	0.1911	50
36491	0.0139	6
202745	0.0102	3
36493	0.0056	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	87.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.47	gold quality
metanephros cortex	UBERON:0010533	81.95	gold quality
spleen	UBERON:0002106	81.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.63	gold quality
adult mammalian kidney	UBERON:0000082	77.39	gold quality
left ovary	UBERON:0002119	77.28	gold quality
ovary	UBERON:0000992	76.09	gold quality
rectum	UBERON:0001052	74.66	gold quality
mucosa of transverse colon	UBERON:0004991	73.68	gold quality
kidney	UBERON:0002113	71.01	gold quality
right ovary	UBERON:0002118	68.53	gold quality
smooth muscle tissue	UBERON:0001135	66.71	gold quality
endometrium	UBERON:0001295	62.52	gold quality
prefrontal cortex	UBERON:0000451	61.94	gold quality
body of stomach	UBERON:0001161	61.33	gold quality
cortex of kidney	UBERON:0001225	60.79	gold quality
muscle tissue	UBERON:0002385	60.78	gold quality
colonic epithelium	UBERON:0000397	60.18	gold quality
liver	UBERON:0002107	60.15	gold quality
right lobe of liver	UBERON:0001114	59.48	gold quality
gall bladder	UBERON:0002110	59.48	gold quality
stomach	UBERON:0000945	59.47	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	58.92	gold quality
skeletal muscle tissue	UBERON:0001134	58.82	gold quality
duodenum	UBERON:0002114	58.36	gold quality
Ammon’s horn	UBERON:0001954	58.33	gold quality
superior frontal gyrus	UBERON:0002661	58.07	gold quality
substantia nigra	UBERON:0002038	57.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	57.67	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	820.74
E-MTAB-3929	yes	581.96
E-MTAB-8271	yes	6.94
E-ANND-3	no	2.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting CRIPTO, 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-3613-3P	100.00	76.36	7965
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-1244	99.33	68.38	832

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 57.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Cripto has dual roles as a coreceptor as well as a coligand for Nodal and that this signaling interaction with Nodal is regulated by an unusual form of glycosylation. (PMID:12052855)
• A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. (PMID:12073012)
• complexation with activin and type II activin receptors and role in blocking activin signaling (PMID:12682303)
• CRIPTO signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells. (PMID:14581455)
• Results suggest that cripto-1 overexpression might be associated with the progression towards a more aggressive phenotype in breast carcinoma, through the activation of both Akt and Smad-2 signalling pathways. (PMID:14584041)
• The regulation of Netrin-1 expression is important in regulating Cripto-1-dependent invasion and migration of mammary epithelial cells. (PMID:16176936)
• The plasma CR-1 might represent a novel biomarker for the detection of breast and colon carcinomas. A statistically significant increase in the levels of plasma CR-1 was found in patients with colon carcinoma and in patients with breast carcinoma. (PMID:16951234)
• CRIPTO-3, a processed pseudogene of CRIPTO-1 on the X chromosome, is expressed in undifferentiated NT2 cells and is regulated by germ cell nuclear factor in parallel to CRIPTO-1 (PMID:16954206)
• Cripto inhibits the tumor suppressor function of TGF-beta by a novel mechanism. (PMID:17030617)
• Transcriptional regulation of CR-1 expression by WNT signaling through an intronic-exonic enhancer element, containing three tandem TCF/LEF binding sites within the CR-1 gene. (PMID:17291450)
• Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration are reported. (PMID:17720976)
• GPI attachment of CR-1 is required for the paracrine activity as a Nodal co-receptor. (PMID:17925387)
• Tese results suggest a differential modulation of CR-1 gene expression in embryonal and colon cancer cells by two different members of the TGF-beta family. (PMID:17941089)
• Cripto facilitates Nodal signaling and inhibits activin signaling by forming receptor complexes with these ligands that are structurally and functionally similar. (PMID:18089557)
• Combined analysis of Cripto-1 and E-cadherin has significant value in evaluating the metastatic potential of gastric cancer and predicting patient prognosis. (PMID:18312357)
• Study indicate that the synthetic h-CFC interacts with the ALK4 receptor with a K(D) in micro M range, that the h-CFC overall topology is determined by the presence of three disulfide bridges. (PMID:19035567)
• Cripto-1 overexpression is involved in the tumorigenesis of gastric- and pancreatobiliary-type intraductal papillary mucinous neoplasms (PMID:19082438)
• Activin A, activin receptor type II, nodal, and cripto mRNA are expressed by eutopic and ectopic endometrium in women with ovarian endometriosis. (PMID:19386982)
• Results show that targeted disruption of the cell surface Cripto/GRP78 complex precludes Cripto activation of MAPK/PI3K and Smad2/3 pathways. (PMID:19421146)
• Cripto-1 overexpression is connected with the tumorigenesis and progression of nasopharyngeal carcinoma. (PMID:19732464)
• work firstly provides human genetic evidence of TDGF1 involved in the pathogenesis of ventricular septal defects (PMID:19853938)
• Nodal and Cripto immunoreactivity increased dramatically in the transition from histologic Grade 1 to histologic Grades 2 and 3 endometrial carcinomas. (PMID:19874624)
• TDGF1 has a role in metachronous metastasis of colorectal cancer (PMID:20126975)
• Data suggest that the up-regulation of CR-1 and p-STAT3 may play important roles in gastric carcinogenesis and lymph node metastasis (PMID:20128024)
• TDGF-1, which is significantly upregulated in APA and mediates aldosterone hypersecretion and deregulated growth in adrenocortical cells in vitro, may represent a key player in the development and pathophysiology of primary aldosteronism. (PMID:20385969)
• Results demonstrate that CR-1 expression is enriched in an undifferentiated, tumorigenic subpopulation and is regulated by key regulators of pluripotent stem cells. (PMID:20549704)
• molecular model of activin receptor-like kinase 4/Cripto/Nodal complex built by homology modeling as well as docking tests aimed at identifying potential binding epitopes (PMID:20629020)
• expression of CR-1 may alter the physiochemical properties of the plasma membrane resulting in an enhancement of intercellular transfer of cellular signaling components which may account for the paracrine activity of CR-1. (PMID:21055389)
• Disturbed expression of endometrial activin A, cripto , and follistatin suggests a dysfunction of the activin pathway in endometriosis/endometrioma. (PMID:21496809)
• Cripto-1 plays a role in the malignant transformation of oral mucosa and is involved in the tumorigenesis and progression of oral squamous cell carcinoma by promoting the growth and migration of malignant cells. (PMID:21824804)
• High CRIPTO-1 is associated with cutaneous melanoma. (PMID:21863025)
• Cripto/GRP78 modulates the TGF-beta pathway in development and oncogenesis [review] (PMID:22306319)
• Cripto-1 may play a role during developmental EMT, and it may also be involved in the reprogramming of differentiated tumor cells into cancer stem cells through the induction of an EMT program. (PMID:22542493)
• Cross-talk between Cripto-1 and the Wnt/beta-catenin signaling pathway might play a role in mammary transformation leading to a more aggressive behavior of mammary cancer cells. (PMID:23022962)
• human testicular tumors showed upregulation of NODAL and CRIPTO that was proportional to invasiveness and to the number of malignant cells. (PMID:23034635)
• Offer some insight into the transcriptional regulation of CR-1 gene expression and its critical role in the pathogenesis of human cancer. (PMID:23129342)
• The significance of cell surface CR-1 expression in human melanoma cells, was examined. (PMID:23574716)
• Cripto is overexpressed in colonic neoplasms and is related to cancer cell migration/invasion. (PMID:24379580)
• These findings clearly suggest that the downregulation of miR-15a-16 with Cripto amplification may be involved in the development of nonsmall cell lung cancer. (PMID:24500260)
• CR-1 expression in glioblastoma multiforme(GBM)tissue and blood; CR-1 plasma levels from GBM patients were elevated compared with normal; CR-1 concentrations higher than normal correlated with shorter overall survival; identified CR-1 in different areas of GBM tissue including perivascular tumor cells and endothelial cells (PMID:24521322)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cripto	ENSMUSG00000032494
rattus_norvegicus	Cripto	ENSRNOG00000037171

Paralogs (5): CFC1 (ENSG00000136698), CFC1B (ENSG00000152093), EGFL7 (ENSG00000172889), CRIPTO3 (ENSG00000225366), EGFL8 (ENSG00000241404)

Protein

Protein identifiers

Protein Cripto — P13385 (reviewed: P13385)

Alternative names: Cripto, EGF-CFC family member, Cripto-1 growth factor, Epidermal growth factor-like cripto protein CR1, Teratocarcinoma-derived growth factor 1

All UniProt accessions (2): P13385, F5H1T8

UniProt curated annotations — full annotation on UniProt →

Function. GPI-anchored cell membrane protein involved in Nodal signaling. Cell-associated CRIPTO acts as a Nodal coreceptor in cis. Shedding of CRIPTO by TMEM8A modulates Nodal signaling by allowing soluble CRIPTO to act as a Nodal coreceptor on other cells. Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm.

Subunit / interactions. Interacts with the activin type-1 receptor ACVR1B.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. Preferentially expressed in gastric and colorectal carcinomas than in their normal counterparts. Expressed in breast and lung.

Post-translational modifications. The GPI-anchor is attached to the protein in the endoplasmic reticulum and serves to target the protein to the cell surface. There, it is processed by GPI processing phospholipase A2 (TMEM8A), removing an acyl-chain at the sn-2 position of GPI and releasing CRIPTO as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D (GPLD1) into a soluble form.

Similarity. Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.

RefSeq proteins (2): NP_001167607, NP_003203* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR017047	Cripto	Family
IPR019011	Cryptic/Cripto_CFC-dom	Domain

Pfam: PF09443

UniProt features (16 total): disulfide bond 6, sequence variant 3, signal peptide 1, chain 1, mutagenesis site 1, propeptide 1, domain 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13385-F1	67.47	0.31

Functional residue map

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

Post-translational modifications (1): 150

Disulfide bonds (6): 128–149, 131–140, 82–89, 83–95, 97–106, 115–133

Glycosylation sites (1): 79

Mutagenesis-validated functional residues (1):

Position	Phenotype
188	alters the localization and decreases the biological activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1433617	Regulation of signaling by NODAL
R-HSA-2892247	POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
R-HSA-1266738	Developmental Biology
R-HSA-452723	Transcriptional regulation of pluripotent stem cells

MSigDB gene sets: 428 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_AXIS_SPECIFICATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_RESPONSE_TO_EPIDERMAL_GROWTH_FACTOR, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY

GO Biological Process (25): blood vessel development (GO:0001568), morphogenesis of a branching structure (GO:0001763), cell migration involved in sprouting angiogenesis (GO:0002042), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), positive regulation of cell population proliferation (GO:0008284), anterior/posterior axis specification, embryo (GO:0008595), embryo development ending in birth or egg hatching (GO:0009792), anterior/posterior pattern specification (GO:0009952), regulation of signal transduction (GO:0009966), positive regulation of endothelial cell migration (GO:0010595), cell differentiation (GO:0030154), positive regulation of cell migration (GO:0030335), mammary gland development (GO:0030879), cellular response to hepatocyte growth factor stimulus (GO:0035729), nodal signaling pathway (GO:0038092), negative regulation of apoptotic process (GO:0043066), positive regulation of MAP kinase activity (GO:0043406), positive regulation of MAPK cascade (GO:0043410), cellular response to fibroblast growth factor stimulus (GO:0044344), cellular response to type II interferon (GO:0071346), cellular response to interleukin-6 (GO:0071354), cellular response to tumor necrosis factor (GO:0071356), cellular response to epidermal growth factor stimulus (GO:0071364), signal transduction (GO:0007165)

GO Molecular Function (5): signaling receptor binding (GO:0005102), growth factor activity (GO:0008083), nodal binding (GO:0038100), activin receptor binding (GO:0070697), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), apical plasma membrane (GO:0016324), membrane raft (GO:0045121), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Developmental Biology	2
Signaling by NODAL	1
Transcriptional regulation of pluripotent stem cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cellular response to growth factor stimulus	2
protein binding	2
membrane	2
vasculature development	1
anatomical structure development	1
anatomical structure morphogenesis	1
multicellular organismal process	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
determination of bilateral symmetry	1
left/right pattern formation	1
animal organ development	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
embryonic axis specification	1
tripartite regional subdivision	1
anterior/posterior axis specification	1
embryo development	1
regionalization	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
cellular developmental process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
gland development	1
response to hepatocyte growth factor	1
activin receptor signaling pathway	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
MAP kinase activity	1

Protein interactions and networks

STRING

1540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRIPTO	ACVR1B	P36896	993
CRIPTO	FMNL1	O95466	973
CRIPTO	ACVR2B	Q13705	968
CRIPTO	GDF3	Q9NR23	964
CRIPTO	NODAL	Q96S42	963
CRIPTO	ACVR1C	Q8NER5	958
CRIPTO	ACVR2A	P27037	938
CRIPTO	HSPA5	P11021	924
CRIPTO	EGF	P01133	915
CRIPTO	LEFTY2	O00292	885
CRIPTO	GDF1	P27539	868
CRIPTO	ZIC3	O60481	808
CRIPTO	NANOG	Q9H9S0	792
CRIPTO	LEFTY1	O75610	786
CRIPTO	SMAD2	Q15796	785

IntAct

14 interactions, top by confidence:

A	B	Type	Score
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
CRIPTO	GPC1	psi-mi:“MI:0915”(physical association)	0.400
CRIPTO	AP2S1	psi-mi:“MI:0915”(physical association)	0.370
CRIPTO	FBLN1	psi-mi:“MI:0915”(physical association)	0.370
CRIPTO	FARSA	psi-mi:“MI:0915”(physical association)	0.370
CRIPTO	ANG	psi-mi:“MI:0915”(physical association)	0.000
CRIPTO	COPS6	psi-mi:“MI:0915”(physical association)	0.000
CRIPTO	GDF9	psi-mi:“MI:0915”(physical association)	0.000
CRIPTO	RIF1	psi-mi:“MI:0915”(physical association)	0.000
CRIPTO	BAG6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (95): WDR26 (Affinity Capture-MS), AIP (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), MAEA (Affinity Capture-MS), RANBP9 (Affinity Capture-MS), RANBP10 (Affinity Capture-MS), RMND5A (Affinity Capture-MS), GID4 (Affinity Capture-MS), GID8 (Affinity Capture-MS), WBP5 (Affinity Capture-MS), ZMYND19 (Affinity Capture-MS), YPEL5 (Affinity Capture-MS), RMND5B (Affinity Capture-MS)

ESM2 similar proteins: A0A060WQA3, A5PMY6, A8WGB1, B4HVU2, B4IXJ2, B4PD96, B4QMF4, D3YXF5, O18738, O35167, O35251, O35348, O43278, O43915, O75339, O89103, P06213, P10643, P13385, P21757, P21758, P51864, P51865, P97946, Q03637, Q05585, Q29243, Q3MI99, Q4LDE5, Q4ZJM7, Q58T08, Q5G872, Q5RAD0, Q5RBP1, Q62165, Q66K08, Q6NZL8, Q6UXH8, Q6UXI9, Q76LD0

Diamond homologs: P0CG36, P0CG37, P13385, P51864, P51865, P97766, Q9I8Q3, O88277, Q5F226, A0A2K5V015, Q5R6R1, Q5T1H1, O97507, Q20911

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
TDGF1	down-regulates	ACVR2A	binding
TDGF1	“down-regulates activity”	TGFB1	binding
TDGF1	down-regulates	MSTN
TDGF1	up-regulates	Skeletal_muscle_differentiation
TDGF1	“up-regulates activity”	NODAL	binding
TDGF1	“up-regulates activity”	ACVR1B	binding
NODAL	“up-regulates quantity by expression”	TDGF1	“transcriptional regulation”
POU5F1	“up-regulates quantity by expression”	TDGF1	“transcriptional regulation”
SOX2/POU5F1	“up-regulates quantity by expression”	TDGF1	“transcriptional regulation”
SOX17/POU5F1	“up-regulates quantity by expression”	TDGF1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	21
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

683 predictions. Top by Δscore:

Variant	Effect	Δscore
3:46579854:G:GG	donor_gain	1.0000
3:46577393:G:GT	donor_gain	0.9900
3:46579093:A:AG	acceptor_gain	0.9900
3:46579094:G:GG	acceptor_gain	0.9900
3:46579852:GA:G	donor_gain	0.9900
3:46579094:GT:G	acceptor_gain	0.9800
3:46577393:G:T	donor_gain	0.9700
3:46579367:G:GG	donor_gain	0.9700
3:46578000:TACAG:T	donor_loss	0.9600
3:46578001:ACAG:A	donor_loss	0.9600
3:46578002:CAG:C	donor_loss	0.9600
3:46578003:AG:A	donor_loss	0.9600
3:46578004:GG:G	donor_loss	0.9600
3:46578005:G:GA	donor_loss	0.9600
3:46578006:T:G	donor_loss	0.9600
3:46579362:GCACA:G	donor_gain	0.9600
3:46579738:GGT:G	acceptor_gain	0.9500
3:46579417:C:CG	donor_gain	0.9400
3:46579738:GGTAA:G	acceptor_gain	0.9400
3:46577392:GGAA:G	donor_gain	0.9300
3:46579094:GTGT:G	acceptor_gain	0.9300
3:46579733:TTTCA:T	acceptor_loss	0.9300
3:46579736:CAG:C	acceptor_loss	0.9300
3:46579417:C:G	donor_gain	0.9100
3:46579738:GGTA:G	acceptor_gain	0.9000
3:46579851:AGA:A	donor_gain	0.9000
3:46579852:GAG:G	donor_gain	0.9000
3:46577377:TGG:T	donor_gain	0.8900
3:46579737:A:AG	acceptor_gain	0.8900
3:46579738:G:GG	acceptor_gain	0.8900

AlphaMissense

1231 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:46579795:T:C	F94L	0.985
3:46579797:T:A	F94L	0.985
3:46579797:T:G	F94L	0.985
3:46579816:T:C	F101L	0.979
3:46579818:C:A	F101L	0.979
3:46579818:C:G	F101L	0.979
3:46579796:T:G	F94C	0.970
3:46579831:T:A	C106S	0.962
3:46579832:G:C	C106S	0.962
3:46579832:G:A	C106Y	0.955
3:46579832:G:T	C106F	0.948
3:46579769:A:T	N85I	0.942
3:46579833:T:G	C106W	0.933
3:46580045:T:C	F145L	0.933
3:46580047:T:A	F145L	0.933
3:46580047:T:G	F145L	0.933
3:46580008:A:C	K132N	0.932
3:46580008:A:T	K132N	0.932
3:46579799:G:A	C95Y	0.927
3:46579823:G:T	G103V	0.927
3:46579762:T:A	C83S	0.925
3:46579763:G:C	C83S	0.925
3:46579804:T:C	C97R	0.923
3:46579780:T:A	C89S	0.921
3:46579781:G:C	C89S	0.921
3:46579781:G:A	C89Y	0.919
3:46579805:G:A	C97Y	0.919
3:46579780:T:C	C89R	0.916
3:46579831:T:C	C106R	0.916
3:46579798:T:A	C95S	0.915

dbSNP variants (sampled 300 via entrez): RS1000142928 (3:46576720 T>C), RS1000179862 (3:46576198 G>A,C,T), RS1000317020 (3:46580557 C>T), RS1000598874 (3:46581382 C>A,G), RS1001281472 (3:46572611 T>C), RS1001423143 (3:46582245 T>G), RS1001517508 (3:46582026 C>G,T), RS1001834465 (3:46578363 T>A), RS1001852897 (3:46580703 C>A), RS1002284110 (3:46574280 T>C), RS1003040779 (3:46574273 A>G), RS1003435234 (3:46579652 AT>A), RS1003461300 (3:46573732 C>G), RS1003696891 (3:46575797 A>G), RS1004291583 (3:46577017 G>T)

Disease associations

OMIM: gene MIM:187395 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant
congenital nervous system disorder	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (2): congenital heart disease (MONDO:0005453), congenital nervous system disorder (MONDO:0002320)

Orphanet (0):

HPO phenotypes

115 total (30 of 115 shown, HPO-id order):

HPO	Term
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000322	Short philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000601	Hypotelorism
HP:0000612	Iris coloboma
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000772	Abnormal rib morphology
HP:0000818	Abnormality of the endocrine system
HP:0000821	Hypothyroidism

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_363	Metabolite levels	3.000000e-06
GCST010002_422	Refractive error	4.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010435	triacylglycerol 56:8 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713025 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	2
trichostatin A	increases expression	1
sodium arsenite	decreases expression, decreases reaction	1
butylbenzyl phthalate	increases expression	1
monoisoamyl-2,3-dimercaptosuccinate	decreases expression, decreases reaction	1
entinostat	increases expression	1
belinostat	increases expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Leflunomide	increases expression	1
Panobinostat	increases expression	1
Acetaminophen	decreases expression	1
Ethanol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Fluorouracil	decreases expression	1
Folic Acid	increases expression	1
Tretinoin	decreases expression, affects binding, increases reaction	1
Triclosan	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE