VEGFC

Chr 4AD

vascular endothelial growth factor C

Also known as: Flt4-L, LMPH1D, LMPHM4, VRP

NCBI Gene: 7424ENSG00000150630UniProt: P49767

The protein is a growth factor that promotes angiogenesis and endothelial cell growth by binding and activating VEGFR-2 and VEGFR-3 receptors, playing a critical role in venous and lymphatic vascular system development during embryogenesis. Mutations cause lymphatic malformation 4, inherited in an autosomal dominant pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.478), indicating intolerance to complete protein loss.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

Lymphatic malformation 4MIM #615907
AD
1
Active trials
94
Pubs (1 yr)
81
P/LP submissions
0%
P/LP missense
0.48
LOEUF
LOF
Mechanism· predicted
Clinical Summary— VEGFC
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.
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ClinVar Variants
79 unique Pathogenic / Likely Pathogenic· 66 VUS of 180 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.48LOEUF
pLI 0.496
Z-score 3.21
OE 0.21 (0.10–0.48)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.85Z-score
OE missense 0.84 (0.75–0.95)
194 obs / 230.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.21 (0.10–0.48)
0≤0.351.4
Missense OE0.84 (0.75–0.95)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 4 / 19.1Missense obs/exp: 194 / 230.2Syn Z: -0.23
DN
0.5673th %ile
GOF
0.3193th %ile
LOF
0.49top 25%

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · LOEUF 0.48

Literature Evidence

LOFIn vitro functional cellular expression assays and studies in zebrafish showed that the mutation resulted in a loss of function without a dominant-negative effect, consistent with haploinsufficiency.PMID:23410910

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

180 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic76
Likely Pathogenic3
VUS66
Likely Benign8
Benign20
Conflicting3
76
Pathogenic
3
Likely Pathogenic
66
VUS
8
Likely Benign
20
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
74
0
76
Likely Pathogenic
0
0
3
0
3
VUS
0
56
10
0
66
Likely Benign
0
1
3
4
8
Benign
0
8
11
1
20
Conflicting
—3
Total2651015176

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

View in ClinVar →

Protein Context — Lollipop Plot

VEGFC · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Alpha-difluoromethylornithine suppresses angiogenesis via the FLI1-CLEC14A-VEGFC pathway in retinal endothelial cells.
Pan JQ et al.·Biochem Biophys Res Commun
2026
LAMP1 enhances DNA-PKcs-mediated AKT phosphorylation and VEGFC secretion to promote lymph node metastasis in esophageal squamous cell carcinoma.
Wang Y et al.·Oncogene
2026
Further characterisation of immortalised human lymphatic endothelial cells to explore their transcriptomic profile and VEGFC response.
Ogmen K et al.·Sci Rep
2025Open Access
Inhibiting VEGFC - mediated hepatocyte - macrophage regulatory axis contributes to protective effects of naringin against high - fat diet - induced hepatic fibrosis.
Li J et al.·Phytomedicine
2026
Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis.
Royo Marco A et al.·Cell Rep
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients