VEGFC

Summary

VEGFC (vascular endothelial growth factor C, HGNC:12682) is a protein-coding gene on chromosome 4q34.3, encoding Vascular endothelial growth factor C (P49767). Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels.

The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors.

Source: NCBI Gene 7424 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphatic malformation 4 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 64 total — 3 pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• MANE Select transcript: NM_005429

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12682
Approved symbol	VEGFC
Name	vascular endothelial growth factor C
Location	4q34.3
Locus type	gene with protein product
Status	Approved
Aliases	VRP, VEGF-C
Ensembl gene	ENSG00000150630
Ensembl biotype	protein_coding
OMIM	601528
Entrez	7424

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000507638, ENST00000618562

RefSeq mRNA: 1 — MANE Select: NM_005429 NM_005429

CCDS: CCDS43285

Canonical transcript exons

ENST00000618562 — 7 exons

Exon	Start	End
ENSE00003724680	176687187	176687520
ENSE00003725398	176729533	176729746
ENSE00003728272	176711499	176711650
ENSE00003730807	176683538	176684040
ENSE00003735477	176687821	176687927
ENSE00003738672	176792165	176792922
ENSE00003751431	176727778	176727968

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 88.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.0695 / max 285.4794, expressed in 1187 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55048	3.3759	770
55047	2.2101	886
55049	1.2274	557
55045	1.0349	488
55046	0.7187	378
55043	0.5612	353
55042	0.5154	346
55050	0.1757	72
55041	0.0852	27
55044	0.0842	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	88.75	gold quality
right lobe of thyroid gland	UBERON:0001119	88.25	gold quality
thyroid gland	UBERON:0002046	87.91	gold quality
left lobe of thyroid gland	UBERON:0001120	87.79	gold quality
omental fat pad	UBERON:0010414	87.05	gold quality
peritoneum	UBERON:0002358	86.99	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.50	gold quality
right lung	UBERON:0002167	85.23	gold quality
decidua	UBERON:0002450	84.99	gold quality
parietal pleura	UBERON:0002400	84.41	gold quality
pleura	UBERON:0000977	83.94	gold quality
visceral pleura	UBERON:0002401	83.68	gold quality
pericardium	UBERON:0002407	83.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.91	gold quality
mammary duct	UBERON:0001765	81.51	gold quality
adipose tissue	UBERON:0001013	81.50	gold quality
connective tissue	UBERON:0002384	81.02	gold quality
thoracic mammary gland	UBERON:0005200	80.97	gold quality
mammary gland	UBERON:0001911	80.84	gold quality
upper lobe of left lung	UBERON:0008952	80.31	gold quality
adrenal tissue	UBERON:0018303	79.99	gold quality
upper lobe of lung	UBERON:0008948	79.77	gold quality
mucosa of urinary bladder	UBERON:0001259	79.74	gold quality
palpebral conjunctiva	UBERON:0001812	79.57	gold quality
parotid gland	UBERON:0001831	78.79	gold quality
lung	UBERON:0002048	78.69	gold quality
epithelium of mammary gland	UBERON:0003244	78.68	gold quality
smooth muscle tissue	UBERON:0001135	78.60	gold quality
endometrium	UBERON:0001295	78.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	2145.32
E-GEOD-135922	yes	38.01
E-ANND-3	yes	6.32
E-MTAB-6678	no	2.42

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, CUX1, ESR1, HDAC1, HIF1A, NFAT5, NFKB1, NKX3-1, NR2F2, NRG1, RUNX2, SIX1, SP1, STAT1, YBX3

miRNA regulators (miRDB)

47 targeting VEGFC, 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-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
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-4666A-3P	99.96	71.71	3434
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6849-5P	99.64	66.00	352
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4743-3P	99.62	68.12	2095

Literature-anchored findings (GeneRIF, showing 40)

• VEGF-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. (PMID:11877295)
• VEGFC expression is closely related to invasion phenotype in cervical carcinomas (PMID:11920583)
• REVIEW:Association of expression of VEGFC and receptors in human leukemia and lymphoma, resulting in the generation of autocrine loops that may support cancer cell survival and proliferation (PMID:11999550)
• Vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C are expressed in human colorectal adenocarcinoma. (PMID:12168824)
• tumor-associated macrophages express VEGF-C-and play a role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer (PMID:12213723)
• VEGF-C mediates cyclic pressure-induced vascular endothelium cell proliferation. (PMID:12388793)
• VEGF-C mainly promotes peri-tumor lymphangiogenesis and has a little effect on angiogenesis. (PMID:12452004)
• Expresssed in gallbladder cancer and is related to lymph node metastasis. (PMID:12469214)
• This factor is up-regulated in breast cancer cells by heregulin-beta; p38/NFKB play a critical role in signal transduction. (PMID:12471041)
• Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. (PMID:12594815)
• Lymphagenesis correlates with increased expression of vascular endothelial growth factor-C in colorectal cancer (PMID:12792749)
• Data demonstrate the expression of vascular endothelial growth factor receptor-3 and vascular endothelial growth factor-C on corneal dendritic cells, which implicate a potential relationship between lymphangiogenesis and leukocyte trafficking in the eye. (PMID:12819011)
• VEGF-C expression is increased in papillary thyroid cancer, compared with paired normal thyroid tissues, but not in other thyroid cancers that are also prone to lymph node metastasis (PMID:12915657)
• Data show that the serine protease plasmin cleaved both propeptides from human vascular endothelial growth factor (VEGF)-D, generating mature forms, and also activated VEGF-C. (PMID:12963694)
• VEGF-C expression in esophageal squamous cell carcinoma may play a role in lymphatic spread (PMID:14534690)
• VEGF-C/flt-4 system can promote vasculogenesis in stroma of breast cancer. The number of Flt-4 positive vessels is closely related to lymph node metastasis. (PMID:14558949)
• Ang2, PIGF and VEGF-C play a role in promote endothelial survival and vascular remodeling by human cytotrophoblast. (PMID:14568550)
• Increased vascular endothelial growth factor C mRNA expression correlates with stage of progression in patients with melanoma (PMID:14676121)
• COX-2 up-regulates VEGF-C and promotes lymphangiogenesis in human lung adenocarcinoma. (PMID:14744769)
• VEGF-C and its receptor FLT-4 play a role in the development of gastric cancer, and the tumors with expression of VEGF-C and FLT-4 are more likely to have lymph node metastasis. (PMID:14760756)
• Her-2/NEU oncogene is essential for the regulation of VEGF-C in ovarian carcinoma; p38 MAPK and NF-kappa B are critically involved in the transcriptional activation of the VEGF-C gene by Her-2/NEU. (PMID:14966375)
• VEGF family proteins regulate wound healing, chronic inflammation and tumour angiogenesis and lymphangiogenesis in fibroblasts. (PMID:15009103)
• The expression of VEGF-C and CCR7 is related to lymph node metastasis of gastric carcinoma and both of them may become new targets for the treatment of gastric carcinoma. (PMID:15040017)
• Expression in esophageal squamous cell carcinomas related to COX-2 expression. Also associated with depth of primary tumor, stage, and probably lymph node metastasis. May assist in management planning. (PMID:15151619)
• intratumoral VEGF-A expression is one of the significant prognostic factors in patients with adenocarcinomas, and that intratumoral VEGF-C expression is one of the significant prognostic factors in patients with squamous cell carcinomas (PMID:15173661)
• furin is responsible for VEGF-C processing in human oral tongue squamous cell carcinoma progression (PMID:15240540)
• VEGF-C expression occurred in 26 of the 68 tumor samples (38%). (PMID:15272284)
• VEGF-C expression may induce lymphangiogenesis in colorectal cancer, as a result, tumor cells can entry the lymphatic vessels easily. (PMID:15484296)
• VEGF-C and VEGF-D are ligands for the integrin alpha9beta1 (PMID:15590642)
• High vascular endothelial growth factor C expression is associated with lymph node metastasis in human pancreatic cancer (PMID:15623620)
• VEGF-C as well as VEGF-A may be involved in the pathogenesis of ovarian endometrioma. (PMID:15668894)
• VEGF-C plays a pivotal role for lymphangiogenesis and tumor growth in gastric cancer (PMID:15756450)
• Increased VEGF-C expression is associated with papillary thyroid cancer (PMID:15870511)
• increased expression of VEGF-C and VEGFR-3 play a role in prostate cancer progression and in metastasis to regional lymph nodes (PMID:15880525)
• VEGF-C expression was detected in 38 out of the 87 patients (43.7%) with primary human breast cancer (PMID:15943035)
• There was a close correlation between the expressions of VEGFR-3, CD31 and prostate tumor metastases. (PMID:16044920)
• Increased expression of VEGF-A and VEGF-C was found in tumor tissues compared to normal epithelium (PMID:16049374)
• Overexpression of vascular endothelial growth factor-C is associated with lung adenocarcinoma (PMID:16116610)
• VEGF-C expression may play a role in lymphangiogenesis of papillary thyroid carcinoma. (PMID:16299237)
• High vascular endothelial growth factor C expression is associated with cervical cancer (PMID:16322297)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	vegfc	ENSDARG00000069640
mus_musculus	Vegfc	ENSMUSG00000031520
rattus_norvegicus	Vegfc	ENSRNOG00000011416

Paralogs (4): VEGFA (ENSG00000112715), PGF (ENSG00000119630), VEGFD (ENSG00000165197), VEGFB (ENSG00000173511)

Protein

Protein identifiers

Vascular endothelial growth factor C — P49767 (reviewed: P49767)

Alternative names: Flt4 ligand, Vascular endothelial growth factor-related protein

All UniProt accessions (1): P49767

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates KDR/VEGFR2 and FLT4/VEGFR3 receptors.

Subunit / interactions. Homodimer; non-covalent and antiparallel. Interacts with FLT4/VEGFR3; the interaction is required for FLT4/VEGFR3 homodimarization and activation.

Subcellular location. Secreted.

Tissue specificity. Expressed in the spleen. Expressed in the lymph node, thymus, appendix and bone marrow. Expressed in the heart, placenta, skeletal muscle, ovary and small intestine. Expressed in the prostate, testis and colon.

Post-translational modifications. Undergoes a complex proteolytic maturation which generates a variety of processed secreted forms with increased activity toward VEGFR-3, but only the fully processed form could activate VEGFR-2. VEGF-C first form an antiparallel homodimer linked by disulfide bonds. Before secretion, a cleavage occurs between Arg-227 and Ser-228 producing a heterotetramer. The next extracellular step of the processing removes the N-terminal propeptide. Finally the mature VEGF-C is composed mostly of two VEGF homology domains (VHDs) bound by non-covalent interactions.

Disease relevance. Lymphatic malformation 4 (LMPHM4) [MIM:615907] A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. LMPHM4 is an autosomal dominant form with onset at birth or in early childhood. Affected individuals manifest lymphedema of lower limbs with prominent veins, and impaired lymphatic uptake and drainage. Additional features are nail dysplasia, skin hyperkeratosis and papillomatosis. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the PDGF/VEGF growth factor family.

RefSeq proteins (1): NP_005420* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000072	PDGF/VEGF_dom	Domain
IPR004153	CXCXC_repeat	Repeat
IPR023581	PD_growth_factor_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily
IPR050507	PDGF/VEGF_growth_factor	Family

Pfam: PF00341, PF03128

UniProt features (26 total): strand 6, disulfide bond 5, repeat 4, glycosylation site 3, propeptide 2, signal peptide 1, mutagenesis site 1, helix 1, chain 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6TJT	X-RAY DIFFRACTION	1.31
2X1W	X-RAY DIFFRACTION	2.7
2X1X	X-RAY DIFFRACTION	3.1
4BSK	X-RAY DIFFRACTION	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49767-F1	73.67	0.21

Functional residue map

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

Disulfide bonds (5): 131–173, 156, 162–209, 165, 166–211

Glycosylation sites (3): 205, 240, 175

Mutagenesis-validated functional residues (1):

Position	Phenotype
227	no proteolytic processing and lower effect on vegfr-2 and vegfr-3.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-194313	VEGF ligand-receptor interactions
R-HSA-195399	VEGF binds to VEGFR leading to receptor dimerization

MSigDB gene sets: 383 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, CHIBA_RESPONSE_TO_TSA_UP, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_BLOOD_PRESSURE, GU_PDEF_TARGETS_DN, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, LU_IL4_SIGNALING, GOBP_RESPONSE_TO_PEPTIDE, SCHWAB_TARGETS_OF_BMYB_POLYMORPHIC_VARIANTS_DN

GO Biological Process (31): response to hypoxia (GO:0001666), sprouting angiogenesis (GO:0002040), positive regulation of neuroblast proliferation (GO:0002052), substrate-dependent cell migration (GO:0006929), signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), response to xenobiotic stimulus (GO:0009410), animal organ morphogenesis (GO:0009887), glial cell proliferation (GO:0014009), morphogenesis of embryonic epithelium (GO:0016331), regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030947), vascular endothelial growth factor signaling pathway (GO:0038084), positive regulation of blood vessel endothelial cell migration (GO:0043536), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of angiogenesis (GO:0045766), negative regulation of blood pressure (GO:0045776), vascular endothelial growth factor receptor signaling pathway (GO:0048010), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of protein secretion (GO:0050714), induction of positive chemotaxis (GO:0050930), positive regulation of cell division (GO:0051781), positive regulation of glial cell proliferation (GO:0060252), positive regulation of mast cell chemotaxis (GO:0060754), positive regulation of lymphangiogenesis (GO:1901492), positive regulation of mesenchymal stem cell proliferation (GO:1902462), cellular response to leukemia inhibitory factor (GO:1990830), angiogenesis (GO:0001525), cell population proliferation (GO:0008283), cell differentiation (GO:0030154), positive regulation of cell migration (GO:0030335), positive chemotaxis (GO:0050918)

GO Molecular Function (5): growth factor activity (GO:0008083), chemoattractant activity (GO:0042056), vascular endothelial growth factor receptor 3 binding (GO:0043185), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), membrane (GO:0016020), platelet alpha granule lumen (GO:0031093)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Signaling by VEGF	1
VEGF ligand-receptor interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
angiogenesis	2
cell population proliferation	2
cell surface receptor protein tyrosine kinase signaling pathway	2
receptor ligand activity	2
cellular anatomical structure	2
response to stress	1
response to decreased oxygen levels	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
cell migration	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to chemical	1
anatomical structure morphogenesis	1
animal organ development	1
gliogenesis	1
morphogenesis of an epithelium	1
embryonic morphogenesis	1
regulation of signal transduction	1
vascular endothelial growth factor receptor signaling pathway	1
regulation of cellular response to growth factor stimulus	1
cellular response to vascular endothelial growth factor stimulus	1
positive regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of blood pressure	1
positive regulation of cell population proliferation	1
epithelial cell proliferation	1

Protein interactions and networks

STRING

2783 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VEGFC	FLT4	P35916	999
VEGFC	KDR	P35968	999
VEGFC	FLT1	P16057	998
VEGFC	NRP2	O60462	996
VEGFC	CCBE1	Q6UXH8	928
VEGFC	LYVE1	Q9Y5Y7	910
VEGFC	NRP1	O14786	894
VEGFC	TEK	Q02763	873
VEGFC	PDGFC	Q9NRA1	864
VEGFC	PROX1	Q92786	822
VEGFC	FGF2	P09038	809
VEGFC	ANGPT2	O15123	795
VEGFC	EPHB4	P54760	763
VEGFC	NFAT5	O94916	759
VEGFC	TIE1	P35590	755

IntAct

12 interactions, top by confidence:

A	B	Type	Score
KDR	VEGFC	psi-mi:“MI:0407”(direct interaction)	0.690
KDR	VEGFC	psi-mi:“MI:0915”(physical association)	0.690
VEGFC	SGTB	psi-mi:“MI:0915”(physical association)	0.560
FLT4	VEGFC	psi-mi:“MI:0915”(physical association)	0.400
VEGFC	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): KDR (Co-crystal Structure), VEGFC (Co-crystal Structure), KDR (Protein-peptide), SGTB (Two-hybrid), VEGFC (Affinity Capture-Western), VEGFC (Reconstituted Complex), VEGFC (Co-fractionation), VEGFC (Co-fractionation)

ESM2 similar proteins: A0A1D5PUP4, A5YT95, O35757, O62650, O75882, O95980, P07225, P09858, P10669, P17247, P19883, P21214, P21674, P26012, P26013, P27090, P30371, P31514, P31515, P47931, P49767, P50291, P61811, P61812, P97299, P97953, Q07257, Q0VBD0, Q17QD6, Q38L25, Q5RA73, Q6NW40, Q6V9H4, Q6ZQ11, Q863H1, Q86X52, Q8BFR2, Q8CI19, Q8JG54, Q8N475

Diamond homologs: B0VXV3, B0VXV4, C0HM96, C0K3N1, C0K3N2, C0K3N3, C0K3N4, C0K3N5, O35251, O35485, O35757, O43915, O73682, P0DL42, P0DW97, P0DW98, P15691, P15692, P16612, P26617, P49151, P49763, P49764, P49765, P49766, P49767, P50412, P52584, P52585, P67860, P67861, P67862, P67863, P67964, P67965, P82475, P83906, P83942, P97946, P97953

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NRP2	up-regulates	VEGFC	binding
VEGFC	up-regulates	NRP2	binding
RUNX2	“up-regulates quantity by expression”	VEGFC	“transcriptional regulation”
bevacizumab	“down-regulates activity”	VEGFC	binding
VEGFC	up-regulates	FLT4	binding
VEGFC	up-regulates	KDR	binding
VEGFC	up-regulates	Angiogenesis

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	40
Likely benign	5
Benign	12

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
140736	NM_005429.5(VEGFC):c.571_572insTT (p.Pro191fs)	Pathogenic
140737	NM_005429.5(VEGFC):c.628C>T (p.Arg210Ter)	Pathogenic
392820	NM_005429.5(VEGFC):c.362-2A>T	Pathogenic

SpliceAI

1547 predictions. Top by Δscore:

Variant	Effect	Δscore
4:176684038:CAG:C	acceptor_gain	1.0000
4:176684041:C:CC	acceptor_gain	1.0000
4:176711497:A:AC	donor_gain	1.0000
4:176711498:C:CC	donor_gain	1.0000
4:176711498:CT:C	donor_gain	1.0000
4:176711648:TAA:T	acceptor_gain	1.0000
4:176711651:C:CC	acceptor_gain	1.0000
4:176729528:CTTA:C	donor_gain	1.0000
4:176729529:TTAC:T	donor_loss	1.0000
4:176729530:TACTT:T	donor_loss	1.0000
4:176729531:A:AC	donor_gain	1.0000
4:176729531:A:T	donor_loss	1.0000
4:176729532:C:CA	donor_gain	1.0000
4:176729532:CT:C	donor_gain	1.0000
4:176729532:CTT:C	donor_gain	1.0000
4:176729532:CTTT:C	donor_gain	1.0000
4:176729532:CTTTT:C	donor_gain	1.0000
4:176729742:TAAGC:T	acceptor_gain	1.0000
4:176729743:AAGC:A	acceptor_gain	1.0000
4:176729744:AGC:A	acceptor_gain	1.0000
4:176729745:GC:G	acceptor_gain	1.0000
4:176729746:CC:C	acceptor_gain	1.0000
4:176729746:CCTG:C	acceptor_loss	1.0000
4:176729747:C:CC	acceptor_gain	1.0000
4:176729748:T:C	acceptor_loss	1.0000
4:176684037:ACAG:A	acceptor_gain	0.9900
4:176684038:CAGC:C	acceptor_gain	0.9900
4:176684039:AG:A	acceptor_gain	0.9900
4:176684040:GC:G	acceptor_loss	0.9900
4:176684041:C:A	acceptor_loss	0.9900

AlphaMissense

2771 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:176687226:C:G	C369S	0.999
4:176687227:A:T	C369S	0.999
4:176687885:C:A	W249C	0.999
4:176687885:C:G	W249C	0.999
4:176727812:C:G	C173S	0.999
4:176727813:A:T	C173S	0.999
4:176727937:G:C	C131W	0.999
4:176727938:C:G	C131S	0.999
4:176727939:A:G	C131R	0.999
4:176727939:A:T	C131S	0.999
4:176727952:C:A	W126C	0.999
4:176727952:C:G	W126C	0.999
4:176687205:A:C	F376C	0.998
4:176687227:A:G	C369R	0.998
4:176711571:C:G	C211S	0.998
4:176711572:A:T	C211S	0.998
4:176711576:G:C	C209W	0.998
4:176711578:A:G	C209R	0.998
4:176727811:G:C	C173W	0.998
4:176727813:A:G	C173R	0.998
4:176727832:G:C	C166W	0.998
4:176727833:C:T	C166Y	0.998
4:176727844:A:C	C162W	0.998
4:176727845:C:G	C162S	0.998
4:176727846:A:G	C162R	0.998
4:176727846:A:T	C162S	0.998
4:176727864:A:G	C156R	0.998
4:176727869:G:T	P154H	0.998
4:176727871:T:A	K153N	0.998
4:176727871:T:G	K153N	0.998

dbSNP variants (sampled 300 via entrez): RS10000057 (4:176768923 G>A,C), RS1000009667 (4:176705612 C>T), RS10000179 (4:176769170 C>A,G,T), RS1000021798 (4:176740714 C>T), RS10000648 (4:176689533 T>A,C), RS1000064987 (4:176692661 A>C), RS1000067401 (4:176698306 A>G), RS10000679 (4:176749810 T>G), RS1000068437 (4:176794898 G>T), RS1000071222 (4:176742412 G>A), RS1000072838 (4:176776057 C>T), RS1000089500 (4:176733890 T>G), RS1000095445 (4:176698078 T>C), RS1000145937 (4:176791326 A>T), RS10001643 (4:176684686 T>A,C,G)

Disease associations

OMIM: gene MIM:601528 | disease phenotypes: MIM:615907

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphatic malformation 4	Strong	Autosomal dominant
lymphatic malformation	Supportive	Autosomal dominant

Mondo (3): lymphatic malformation 4 (MONDO:0014393), lymphedema (MONDO:0019297), lymphatic malformation (MONDO:0019313)

Orphanet (2): Milroy disease (Orphanet:79452), OBSOLETE: Lymphedema (Orphanet:79383)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000034	Hydrocele testis
HP:0000962	Hyperkeratosis
HP:0001004	Lymphedema
HP:0001015	Prominent superficial veins
HP:0010741	Pedal edema
HP:0011463	Childhood onset
HP:0100658	Cellulitis
HP:0100797	Toenail dysplasia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001352_1	HIV-1 viral setpoint	2.000000e-07
GCST003989_18	Chin dimples	3.000000e-15
GCST005588_25	Idiopathic dilated cardiomyopathy	9.000000e-06
GCST005988_4	Serum albumin levels	6.000000e-09
GCST005989_11	Serum total protein levels	4.000000e-09
GCST006412_44	Intraocular pressure	6.000000e-09
GCST006585_1266	Blood protein levels	1.000000e-117
GCST009725_75	Intraocular pressure	6.000000e-08
GCST010653_10	Thyroid stimulating hormone levels	3.000000e-09
GCST012017_1	Mastocytosis (KIT D816V positive)	2.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006319	HIV viral set point measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008209	Lymphedema	C15.604.496

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3714157 (SINGLE PROTEIN)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4604006	VEGFC	3	5.50	1	sorafenib
rs7664413	VEGFA, VEGFC		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	decreases expression, increases expression, affects cotreatment, affects expression	4
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
(+)-JQ1 compound	affects cotreatment, decreases expression	3
Sunitinib	decreases expression, increases expression	3
Copper	affects binding, increases expression, decreases expression	3
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	2
bisphenol A	increases expression, affects cotreatment	2
cobaltous chloride	decreases expression	2
SAR131675	decreases reaction, increases phosphorylation	2
Vorinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance, decreases methylation	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Estradiol	increases expression, decreases expression, affects cotreatment	2
Mustard Gas	affects reaction, decreases expression, affects expression	2
Oxygen	decreases reaction, increases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Valproic Acid	decreases expression, increases expression	2
tert-Butylhydroperoxide	increases expression, increases secretion	2
Particulate Matter	decreases expression, increases abundance, decreases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases methylation	1
4-oxoretinoic acid	decreases expression	1
urushiol	increases expression	1
lead acetate	increases expression	1
methylselenic acid	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
IMOL S-140	decreases expression	1
terbufos	increases methylation	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7U2	SEES3-1V human VEGFC, clone1	Embryonic stem cell	Male
CVCL_A7U3	SEES3-1V human VEGFC, clone2	Embryonic stem cell	Male
CVCL_A7U4	SEES3-1V human VEGFC, clone3	Embryonic stem cell	Male
CVCL_B8RN	Abcam HCT 116 VEGFC KO	Cancer cell line	Male
CVCL_B9U3	Abcam A-549 VEGFC KO	Cancer cell line	Male
CVCL_E0SV	Ubigene HeLa VEGFC KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00852930	PHASE4	COMPLETED	Low Level Laser Treatment and Breast Cancer Related Lymphedema
NCT01068431	PHASE4	COMPLETED	Short Term Effectiveness Study of Juxta-Fit Versus Trico Bandages in the Treatment of Leg Lymphedema
NCT02257970	PHASE4	COMPLETED	Lymphedema Study for Arm or Leg Lymphedema
NCT02375945	PHASE4	COMPLETED	Comparison Between a Non-elastic Falcro Device and Current Method After Total Knee Arthroplasty
NCT03584633	PHASE4	COMPLETED	Effect of Exercise on Indocyanine Green (ICG) Lymphography Imaging
NCT07285005	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Efficacy and Safety of KP-001 Compared With Placebo in Patients Aged ≥2 Years With Common VM, Common LM, or KTS/CLOVES Syndrome
NCT00028951	PHASE3	COMPLETED	Fibrin Sealant in Decreasing Lymphedema Following Surgery to Remove Lymph Nodes in Patients With Cancer of the Vulva
NCT00201890	PHASE3	COMPLETED	Trial of Decongestive Lymphatic Therapy for Lymphedema in Women With Breast Cancer DELTA STUDY
NCT00577317	PHASE3	TERMINATED	Flexitouch® Home Maintenance Therapy or Standard Home Maintenance Therapy in Treating Patients With Lower-Extremity Lymphedema Caused by Treatment for Cervical Cancer, Vulvar Cancer, or Endometrial Cancer
NCT02927496	PHASE3	COMPLETED	A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali
NCT02929121	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in India
NCT02929134	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in Sri Lanka
NCT04228991	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated LocoRegional Radiotherapy in Breast Cancer
NCT06144164	PHASE3	RECRUITING	A Study of a Comprehensive Prevention Program to Reduce Lymphedema After Axillary Lymph Node Dissection in People With Breast Cancer
NCT02335242	PHASE2	COMPLETED	Sildenafil for the Treatment of Lymphatic Malformations
NCT03243019	PHASE2	RECRUITING	Efficacy of Rapamycin in the Treatment of Cervico-facial Lymphatic Malformations
NCT03427619	PHASE2	COMPLETED	OK432 (Picibanil) in the Treatment of Lymphatic Malformations
NCT03972592	PHASE2	COMPLETED	Topical Sirolimus in Cutaneous Lymphatic Malformations
NCT04861064	PHASE2	RECRUITING	Weekly Sirolimus Therapy
NCT05871970	PHASE2	RECRUITING	Safety and Efficacy Study of Intracystic TARA-002 for the Treatment of Lymphatic Malformations in Participants 6 Months to Less Than 18 Years of Age
NCT05983159	PHASE2	RECRUITING	A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
NCT06437158	PHASE2	RECRUITING	Use of Bleomycin in the Sclerotherapy of Lymphatic Malformations for Pediatric Patients
NCT06789913	PHASE2	RECRUITING	A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation
NCT00022204	PHASE2	COMPLETED	Vitamin E and Pentoxifylline in Treating Women With Lymphedema After Radiation Therapy for Breast Cancer
NCT00058851	PHASE2	COMPLETED	Massage Therapy for Breast Cancer Treatment-Related Swelling of the Arms
NCT00064857	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema of the Arm in Breast Cancer Survivors
NCT00077090	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy Compared With Standard Therapy in Treating Chronic Arm Lymphedema in Patients Who Have Undergone Radiation Therapy for Cancer
NCT00155220	PHASE2	UNKNOWN	Treatment of Lymphedema: Application of the Kinesio Taping
NCT00188604	PHASE2	COMPLETED	The Use of Selenium to Treat Secondary Lymphedema - Breast Cancer
NCT00214032	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema
NCT00589121	PHASE2	COMPLETED	Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg
NCT00827372	PHASE2	COMPLETED	A Study of Vascular Endothelial Growth Factor (VEGF) Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer
NCT01003951	PHASE2	COMPLETED	Acupuncture for the Treatment of Chronic Lymphedema
NCT01276054	PHASE2	TERMINATED	Sentinel and/or Axillary Lymph Node Biopsy With or Without Axillary Reverse Mapping in Reducing Incidence and Severity of Arm Lymphedema in Stage 0-2 Patients.
NCT01318785	PHASE2	UNKNOWN	Therapeutical Assessment of Compression Armsleeves for Lymphatic Indications
NCT01406769	PHASE2	COMPLETED	Bioimpedance Spectroscopy in Detecting Lower-Extremity Lymphedema in Patients With Stage I, Stage II, Stage III, or Stage IV Vulvar Cancer Undergoing Surgery and Lymphadenectomy
NCT02700529	PHASE2	COMPLETED	Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)
NCT02895724	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy to Reduce Lymphedema After Breast Cancer -an Explorative Clinical Trial
NCT03658967	PHASE2	COMPLETED	Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)
NCT03776721	PHASE2	COMPLETED	Treatment of Breast Cancer-related Lymphedema With Stem Cells and Fat Grafting