FOXC2

Summary

FOXC2 (forkhead box C2, HGNC:3801) is a protein-coding gene on chromosome 16q24.1, encoding Forkhead box protein C2 (Q99958). Transcriptional activator. It is haploinsufficient (ClinGen: sufficient evidence).

This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the development of mesenchymal tissues.

Source: NCBI Gene 2303 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphedema-distichiasis syndrome (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 302 total — 36 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 30 downstream targets (CollecTRI)
• MANE Select transcript: NM_005251

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3801
Approved symbol	FOXC2
Name	forkhead box C2
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	MFH-1
Ensembl gene	ENSG00000176692
Ensembl biotype	protein_coding
OMIM	602402
Entrez	2303

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000649859

RefSeq mRNA: 1 — MANE Select: NM_005251 NM_005251

CCDS: CCDS10958

Canonical transcript exons

ENST00000649859 — 1 exons

Exon	Start	End
ENSE00003833813	86566829	86569728

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 93.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9503 / max 173.0338, expressed in 945 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155448	6.4238	897
155450	0.7182	391
155449	0.3904	228
155451	0.2134	111
155452	0.2045	116

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	93.01	gold quality
palpebral conjunctiva	UBERON:0001812	89.87	gold quality
popliteal artery	UBERON:0002250	89.82	gold quality
trigeminal ganglion	UBERON:0001675	89.79	gold quality
tibial artery	UBERON:0007610	89.77	gold quality
urethra	UBERON:0000057	89.28	gold quality
aorta	UBERON:0000947	89.14	gold quality
ascending aorta	UBERON:0001496	88.45	gold quality
thoracic aorta	UBERON:0001515	88.28	gold quality
dorsal root ganglion	UBERON:0000044	87.75	gold quality
descending thoracic aorta	UBERON:0002345	87.10	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.67	silver quality
heart right ventricle	UBERON:0002080	84.07	silver quality
right coronary artery	UBERON:0001625	83.62	gold quality
left coronary artery	UBERON:0001626	83.32	gold quality
cartilage tissue	UBERON:0002418	83.20	gold quality
coronary artery	UBERON:0001621	82.81	gold quality
saphenous vein	UBERON:0007318	82.43	gold quality
buccal mucosa cell	CL:0002336	81.81	gold quality
endothelial cell	CL:0000115	81.62	silver quality
tibia	UBERON:0000979	81.52	gold quality
trabecular bone tissue	UBERON:0002483	80.39	gold quality
epithelial cell of pancreas	CL:0000083	80.25	silver quality
upper arm skin	UBERON:0004263	79.79	gold quality
mucosa of paranasal sinus	UBERON:0005030	79.77	gold quality
sperm	CL:0000019	79.41	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.32	gold quality
pancreatic ductal cell	CL:0002079	78.30	silver quality
tibialis anterior	UBERON:0001385	78.20	silver quality
tibial nerve	UBERON:0001323	77.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.55

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

30 targets.

Target	Regulation
ADAM2
AKT1
ANGPT2	Unknown
BRD2
CCL3L1
CDH1
CP
CTNNB1	Activation
CTNND1
CXCR4	Activation
DES	Activation
DLL1	Unknown
DLL4	Activation
FGF8
HAND1	Activation
HEY1	Activation
HEY2	Activation
IGF2
IL3
INS
ITGB1
ITGB3	Unknown
KDR	Activation
MT-ATP6
MYOD1
PAX1	Unknown
PRKAR1A
SERPINE1	Unknown
TGFB1	Activation
ZBED6

JASPAR motifs

Motif	Name	Family
MA0846.1	FOXC2	FOX
MA0846.2	FOXC2	FOX

JASPAR matrix evidence (PMIDs): PMID:23354101

Upstream regulators (CollecTRI, top): BRCA1, GATA3, GLI2, GSC, KMT2A, MEOX1

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• FOXC2 mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations. (PMID:11694548)
• Analysis of phenotypic abnormalities in lymphedema-distichiasis syndrome patients with causative FOXC2 mutations suggests a possible developmental role for FOXC2 in both venous and lymphatic systems. (PMID:12114478)
• Sequencing of the coding region of the only translated exon of the FOXC2 gene revealed a C to A transversion at position 939 resulting in a Tyr313Stop codon with premature termination of translation and a truncated protein product. (PMID:12383817)
• Mutation screening of the FOXC2 gene identified a common polymorphism in the 5’ untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity. (PMID:12453913)
• An out-of-frame deletion (914-921del) was identified and found to segregate with distichiasis-lymphedema syndrome, further highlighting the phenotypic heterogeneity of lymphedema conditions linked to FOXC2 truncating mutations (PMID:12485195)
• absence of evidence for the association of three frequent single nucleotide polymorphisms and four common haplotypes with Japanese type 2 diabetes (PMID:12540636)
• Genetic variations of this protein occur in Pima Indians. (PMID:12716768)
• FOXC2 -512C>T variant is not associated with Type 2 diabetes. (PMID:14530861)
• adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity (PMID:15198934)
• data suggest that transcription factor FOXC2 is a weak but consistent candidate gene for obesity and dyslipidemia (PMID:15601967)
• These findings demonstrate an important role of adipocyte-expressed FOXC2 on whole-body glucose metabolism. (PMID:15919786)
• FOXC2 missense mutations identified as functional nulls in patients with hereditary lymphedema with distichiasis. (PMID:16081467)
• Foxc2 is a key molecule to regulate PAI-1 gene expression. (PMID:16456100)
• Results suggest that FOXC2 is a susceptibility locus for reduced BMD in Japanese men and women. (PMID:16786163)
• these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. (PMID:16952980)
• Every participant with a mutation in FOXC2 showed reflux in the great saphenous vein. FOXC2 appears to be important for the normal development and maintenance of venous and lymphatic valves. (PMID:17372167)
• FOXC2 plays a key role in metastasis and is associated with aggressive basal-like breast tumors. (PMID:17537911)
• confirmation that of the primary lymphoedemas, only lymphoedema with distichiasis is caused by FOXC2 mutations [Fox2C] (PMID:18197197)
• family with classical lymphedema-distichiasis syndrome caused by a duplication in the FOXC2-gene (PMID:18986489)
• lymphedema-distichiasis disorder is linked to a novel missense mutation in a patient (PMID:19013876)
• Forkhead transcription factor Foxc2 directly regulates expression of genes involved in angiogenesis: CXCR4, integrin beta3, Delta-like 4 (Dll4), and angiopoietin 2. Foxc2 is a regulator of vascular formation and remodeling. (PMID:19185813)
• Expression of FOXC2 was significantly decreased in three samples from familial combined hyperlipidaemia compared to controls. (PMID:19339011)
• Mutations in the VEGFR3 and FOXC2 genes account for a subset of patients with unexplained in utero generalized subcutaneous edema and hydrops fetalis without family history of lymphedema (PMID:19394045)
• Decreased FOXC2 expression were shown in the lymphatic endothelial cells of the jugular lymphatic sacs of the trisomic fetuses. (PMID:19548265)
• The FOXC2 gene in 288 patients with primary lymphedema was analyzed and 11 pathogenic mutations, of which 9 are novel, were found. (PMID:19760751)
• Foxc2 may have regulatory functions independent of its nuclear transcriptional activity. (PMID:19935708)
• these findings demonstrate that haplodeficiency of Foxc2 results in impaired formation of tumor blood vessels as well as reduced tumor growth and thereby provide evidence that Foxc2 is critical for tumor development and angiogenesis. (PMID:20060810)
• Chromosome 16 duplication upstream of FOXC2 is associated with lymphedema-distichiasis syndrome without FOXC2 mutation. (PMID:20218083)
• Here we describe a case of lymphedema carrying a de novo frameshift mutation of FOXC2 who presented a prepubertal onset of lower limbs lymphedema and mild distichiasis associated with other anomalies such as webbing neck and ptosis. (PMID:20450314)
• FOXC2 mediates the transcriptional repression of p120 catenin in non-small cell lung cancer cells. (PMID:20460685)
• The Q100X mutation in FOXC2 is the genetic defect underlying the lymphedema-distichiasis syndrome in a family that also exhibits high prevalence of spinal extradural arachnoid cysts. (PMID:20535019)
• A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome. (PMID:20552815)
• High-FOXC2 expression is associated with esophageal squamous cell carcinoma. (PMID:20803080)
• the current findings identify a previously unknown role for Foxc2 as an important metabo-regulator of mitochondrial morphology and metabolism. (PMID:21270254)
• de novo mutations and rare variants in hypoplastic left heart syndrome for FOXC2 gene (PMID:21457232)
• FOXC2 mutations cause a functional failure of dermal initial lymphatics during gravitational stress (dependency), but not hypoplasia. (PMID:21464574)
• Results indicate that Foxc2 plays an important role in osteoblastogenesis by promoting osteoblast proliferation, survival and differentiation through up-regulation of integrin beta1 in response to stimuli which induce bone formation. (PMID:21640215)
• This family study illustrates that a hereditary form of lymphedema, caused by a FOXC2 mutation, can cause severe hydrops fetalis and neonatal pulmonary lymphangiectasis. (PMID:21918810)
• Increased expression of Foxc2 was observed in 27.7% of primary NSCLC tumors. Overexpression of Foxc2 in stage I NSCLC was associated with a worse overall survival and correlated with a shorter recurrence-free survival. (PMID:22178381)
• FOXC2 expression was significantly correlatd with the degree of lymph node metastasis in colorectal cancer. (PMID:22216698)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Foxc2	ENSMUSG00000046714
rattus_norvegicus	Foxc2	ENSRNOG00000047446
drosophila_melanogaster	croc	FBGN0014143

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein C2 — Q99958 (reviewed: Q99958)

Alternative names: Forkhead-related protein FKHL14, Mesenchyme fork head protein 1, Transcription factor FKH-14

All UniProt accessions (1): Q99958

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylation regulates FOXC2 transcriptional activity by promoting its recruitment to chromatin.

Disease relevance. Lymphedema-distichiasis syndrome (LPHDST) [MIM:153400] An autosomal dominant disorder characterized by primary limb lymphedema associated with distichiasis (double rows of eyelashes, with extra eyelashes growing from the Meibomian gland orifices). Swelling of the extremities, due to altered lymphatic flow, usually appears in late childhood or puberty. Most affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia. Drooping of the upper eyelid (ptosis) is a variable feature of the lymphedema-distichiasis syndrome, occurring in about 30% of patients. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_005242* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047391	FOXC1/C2-like_FH	Domain
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (36 total): modified residue 13, helix 5, strand 5, compositionally biased region 4, region of interest 3, cross-link 2, sequence variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6AKP	X-RAY DIFFRACTION	2.32
6AKO	X-RAY DIFFRACTION	2.4
9VRQ	X-RAY DIFFRACTION	2.8
6LBM	X-RAY DIFFRACTION	2.84
6O3T	X-RAY DIFFRACTION	3.06
1D5V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99958-F1	56.45	0.16

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 (15): 219, 232, 235, 240, 247, 251, 279, 281, 288, 293, 367, 458, 184, 214, 215

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9761174	Formation of intermediate mesoderm
R-HSA-9830674	Formation of the ureteric bud

MSigDB gene sets: 385 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_METANEPHROS_DEVELOPMENT, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH

GO Biological Process (50): negative regulation of transcription by RNA polymerase II (GO:0000122), ossification (GO:0001503), branching involved in blood vessel morphogenesis (GO:0001569), metanephros development (GO:0001656), ureteric bud development (GO:0001657), somitogenesis (GO:0001756), lymphangiogenesis (GO:0001946), blood vessel remodeling (GO:0001974), apoptotic process involved in outflow tract morphogenesis (GO:0003275), regulation of transcription by RNA polymerase II (GO:0006357), Notch signaling pathway (GO:0007219), mesoderm development (GO:0007498), heart development (GO:0007507), insulin receptor signaling pathway (GO:0008286), anatomical structure morphogenesis (GO:0009653), response to hormone (GO:0009725), positive regulation of endothelial cell migration (GO:0010595), neural crest cell development (GO:0014032), cell differentiation (GO:0030154), collagen fibril organization (GO:0030199), positive regulation of cell adhesion mediated by integrin (GO:0033630), embryonic heart tube development (GO:0035050), positive regulation of vascular wound healing (GO:0035470), camera-type eye development (GO:0043010), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of organ growth (GO:0046620), vascular endothelial growth factor receptor signaling pathway (GO:0048010), paraxial mesodermal cell fate commitment (GO:0048343), embryonic viscerocranium morphogenesis (GO:0048703), artery morphogenesis (GO:0048844), ventricular cardiac muscle tissue morphogenesis (GO:0055010), cardiac muscle cell proliferation (GO:0060038), glomerular endothelium development (GO:0072011), podocyte differentiation (GO:0072112), glomerular mesangial cell development (GO:0072144), positive regulation of cell migration involved in sprouting angiogenesis (GO:0090050), blood vessel diameter maintenance (GO:0097746), negative regulation of cold-induced thermogenesis (GO:0120163), negative regulation of apoptotic process involved in outflow tract morphogenesis (GO:1902257)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin DNA binding (GO:0031490), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gastrulation	1
Kidney development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription cis-regulatory region binding	3
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 formation involved in morphogenesis	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor activity	2
DNA binding	2
chromatin binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
multicellular organismal process	1
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
kidney development	1
mesonephric tubule development	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
somite development	1
anatomical structure morphogenesis	1
lymph vessel morphogenesis	1
tissue remodeling	1
outflow tract morphogenesis	1
apoptotic process involved in heart morphogenesis	1
cell surface receptor signaling pathway	1
tissue development	1
animal organ development	1
circulatory system development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
developmental process	1
anatomical structure development	1
response to endogenous stimulus	1
response to chemical	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
neural crest cell differentiation	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXC2	SOX18	P35713	829
FOXC2	FLT4	P35916	824
FOXC2	SNAI1	O95863	813
FOXC2	ZEB1	P37275	795
FOXC2	GJC2	Q5T442	780
FOXC2	TCF15	Q12870	741
FOXC2	EFNB2	P52799	734
FOXC2	VEGFC	P49767	727
FOXC2	ITGA9	Q13797	704
FOXC2	SNAI2	O43623	696
FOXC2	TWIST1	Q15672	688
FOXC2	RBPJ	Q06330	682
FOXC2	NFATC1	O95644	678
FOXC2	LYVE1	Q9Y5Y7	676
FOXC2	CTNNB1	P35222	675

IntAct

32 interactions, top by confidence:

A	B	Type	Score
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
TRIM27	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
TAX1BP1	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
FOXC2	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
FOXC2	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
FOXC2	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.560
RBPMS	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
FOXC2	KRTAP3-3	psi-mi:“MI:0915”(physical association)	0.560
METTL27	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
PPP2R2A	FOXC2	psi-mi:“MI:0915”(physical association)	0.560
FOXC2	FOXC2	psi-mi:“MI:0915”(physical association)	0.500
FOXC2	LYAR	psi-mi:“MI:0915”(physical association)	0.400
PIN1	FOXC2	psi-mi:“MI:0915”(physical association)	0.400
PPP2R1A	INTS2	psi-mi:“MI:0914”(association)	0.350
PPP2R2A	RBM7	psi-mi:“MI:0914”(association)	0.350
FOXC1	NFIX	psi-mi:“MI:0914”(association)	0.350
FOXC2	ZNF536	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
FOXC2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.000
FOXC2	KRTAP3-3	psi-mi:“MI:0915”(physical association)	0.000
FOXC2	METTL27	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): TRIM27 (Two-hybrid), TAX1BP1 (Two-hybrid), RBPMS (Two-hybrid), CNOT7 (Two-hybrid), FOXC2 (Affinity Capture-MS), FOXC2 (Affinity Capture-MS), FOXC2 (Affinity Capture-MS), FOXC1 (Affinity Capture-MS), HOXD13 (Affinity Capture-MS), FOXC2 (Affinity Capture-MS), HOXC13 (Affinity Capture-MS), SATB2 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), ZBTB34 (Affinity Capture-MS), C5orf24 (Affinity Capture-MS)

ESM2 similar proteins: A0A8V0YY16, A0JPN1, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A2T7J2, A7MB54, A8MTJ6, B5RHS5, D3Z120, O54743, O88470, P14653, P17919, P32183, P35584, P46153, P55316, P55318, P56260, P78411, P81067, P81068, Q00939, Q12947, Q12948, Q12951, Q14774, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q3I5G5, Q3Y598, Q60987, Q61080

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
BRCA1	“down-regulates quantity by repression”	FOXC2	“transcriptional regulation”
GATA3	“down-regulates quantity by repression”	FOXC2	“transcriptional regulation”
CDK5	“up-regulates activity”	FOXC2	phosphorylation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	19
Uncertain significance	189
Likely benign	34
Benign	10

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032303	NM_005251.3(FOXC2):c.973del (p.Ala325fs)	Pathogenic
1451572	NM_005251.3(FOXC2):c.595dup (p.His199fs)	Pathogenic
1694803	NM_005251.3(FOXC2):c.902_920del (p.Leu301fs)	Pathogenic
1711416	NM_005251.3(FOXC2):c.558del (p.Pro188fs)	Pathogenic
2031286	NM_005251.3(FOXC2):c.227_230dup (p.Tyr77Ter)	Pathogenic
2584485	NM_005251.3(FOXC2):c.908_923dup (p.Pro309fs)	Pathogenic
2632840	NM_005251.3(FOXC2):c.943C>T (p.Gln315Ter)	Pathogenic
280261	NM_005251.3(FOXC2):c.988dup (p.Gln330fs)	Pathogenic
3243628	NC_000016.9:g.(?86544176)(86602447_?)del	Pathogenic
3641572	NM_005251.3(FOXC2):c.914_921dup (p.Ala308fs)	Pathogenic
449991	NM_005251.3(FOXC2):c.130del (p.His44fs)	Pathogenic
4531622	NM_005251.3(FOXC2):c.625A>T (p.Lys209Ter)	Pathogenic
4531623	NM_005251.3(FOXC2):c.646G>T (p.Glu216Ter)	Pathogenic
4712155	NM_005251.3(FOXC2):c.835C>T (p.Arg279Ter)	Pathogenic
4714552	NM_005251.3(FOXC2):c.756del (p.Asp253fs)	Pathogenic
4734355	NM_005251.3(FOXC2):c.382G>T (p.Glu128Ter)	Pathogenic
523810	NM_005251.3(FOXC2):c.712C>T (p.Gln238Ter)	Pathogenic
524132	NM_005251.3(FOXC2):c.902_923del (p.Leu301fs)	Pathogenic
599243	NM_005251.3(FOXC2):c.122A>T (p.Tyr41Phe)	Pathogenic
599244	NM_005251.3(FOXC2):c.1205C>T (p.Pro402Leu)	Pathogenic
599245	NM_005251.3(FOXC2):c.1258C>T (p.Gln420Ter)	Pathogenic
7250	NM_005251.3(FOXC2):c.1090_1093dup (p.Pro365fs)	Pathogenic
7252	NM_005251.3(FOXC2):c.1331del (p.Gln444fs)	Pathogenic
7253	NM_005251.3(FOXC2):c.209dup (p.Val71fs)	Pathogenic
7254	NM_005251.3(FOXC2):c.200_201dup (p.Lys68fs)	Pathogenic
7255	NM_005251.3(FOXC2):c.588dup (p.Thr197fs)	Pathogenic
7256	NM_005251.3(FOXC2):c.509del (p.Lys170fs)	Pathogenic
7257	NM_005251.3(FOXC2):c.914_921del (p.Tyr305fs)	Pathogenic
7258	NM_005251.3(FOXC2):c.1006dup (p.Met336fs)	Pathogenic
7259	NM_005251.3(FOXC2):c.602_681delinsACAAA (p.Ala201_Thr226delinsAsp)	Pathogenic

SpliceAI

2 predictions. Top by Δscore:

Variant	Effect	Δscore
16:86568865:C:CA	acceptor_gain	0.4000
16:86568866:G:A	acceptor_gain	0.2200

AlphaMissense

3259 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:86567549:A:C	K72Q	1.000
16:86567549:A:G	K72E	1.000
16:86567550:A:C	K72T	1.000
16:86567550:A:T	K72M	1.000
16:86567551:G:C	K72N	1.000
16:86567551:G:T	K72N	1.000
16:86567552:C:A	P73T	1.000
16:86567552:C:T	P73S	1.000
16:86567553:C:A	P73Q	1.000
16:86567553:C:G	P73R	1.000
16:86567553:C:T	P73L	1.000
16:86567556:C:A	P74H	1.000
16:86567556:C:G	P74R	1.000
16:86567558:T:A	Y75N	1.000
16:86567558:T:C	Y75H	1.000
16:86567558:T:G	Y75D	1.000
16:86567561:A:C	S76R	1.000
16:86567561:A:T	S76C	1.000
16:86567562:G:A	S76N	1.000
16:86567562:G:T	S76I	1.000
16:86567563:C:A	S76R	1.000
16:86567563:C:G	S76R	1.000
16:86567564:T:A	Y77N	1.000
16:86567564:T:C	Y77H	1.000
16:86567564:T:G	Y77D	1.000
16:86567565:A:G	Y77C	1.000
16:86567567:A:T	I78F	1.000
16:86567568:T:A	I78N	1.000
16:86567568:T:C	I78T	1.000
16:86567568:T:G	I78S	1.000

dbSNP variants (sampled 300 via entrez): RS1000879434 (16:86568550 T>C), RS1000885020 (16:86565319 C>G,T), RS1000932489 (16:86566247 T>G), RS1000961957 (16:86566463 A>T), RS1001606406 (16:86565254 T>C), RS1001759738 (16:86569365 A>T), RS1002290656 (16:86566861 C>A,T), RS1002424616 (16:86566703 C>G), RS1002762369 (16:86568256 C>G,T), RS1002961765 (16:86569940 G>A,T), RS1003097276 (16:86569671 G>A,C,T), RS1003293974 (16:86568694 G>A), RS1003431373 (16:86567995 G>A,C), RS1003840590 (16:86565945 C>G,T), RS1003892950 (16:86565817 G>A)

Disease associations

OMIM: gene MIM:602402 | disease phenotypes: MIM:153400, MIM:236750

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphedema-distichiasis syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
lymphedema-distichiasis syndrome	Definitive	AD

Mondo (2): lymphedema-distichiasis syndrome (MONDO:0007922), non-immune hydrops fetalis (MONDO:0009369)

Orphanet (2): Lymphedema-distichiasis syndrome (Orphanet:33001), Non-immune hydrops fetalis (Orphanet:363999)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000075	Renal duplication
HP:0000093	Proteinuria
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000347	Micrognathia
HP:0000465	Webbed neck
HP:0000476	Cystic hygroma
HP:0000495	Recurrent corneal erosions
HP:0000508	Ptosis
HP:0000509	Conjunctivitis
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000613	Photophobia
HP:0000656	Ectropion
HP:0000819	Diabetes mellitus
HP:0001004	Lymphedema
HP:0001324	Muscle weakness
HP:0001581	Recurrent skin infections
HP:0001629	Ventricular septal defect
HP:0001636	Tetralogy of Fallot
HP:0001643	Patent ductus arteriosus
HP:0001790	Nonimmune hydrops fetalis
HP:0001970	Tubulointerstitial nephritis
HP:0002619	Varicose veins
HP:0002808	Kyphosis
HP:0003011	Abnormality of the musculature
HP:0003550	Predominantly lower limb lymphedema
HP:0004930	Abnormality of the pulmonary vasculature

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003999_21	Nose size	2.000000e-07
GCST004025_25	Systemic juvenile idiopathic arthritis	5.000000e-06
GCST004230_1	Sepsis in extremely premature infants	1.000000e-07
GCST009356_15	Nonsyndromic cleft palate	9.000000e-11
GCST009391_1555	Metabolite levels	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009776	ornithine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537710	Lymphedema distichiasis syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465348 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases reaction	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	increases expression	2
Tretinoin	decreases expression, affects cotreatment, decreases reaction, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression, affects reaction	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, affects expression	2
TAK-243	decreases sumoylation	1
methylmercuric chloride	increases expression	1
dimethylselenide	increases oxidation, decreases expression	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
tobacco tar	decreases expression, decreases reaction	1
diallyl disulfide	decreases reaction, decreases expression	1
cupric chloride	increases expression	1
doxylamine succinate	decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
Chir 99021	affects cotreatment, increases expression, decreases reaction	1
belinostat	increases expression	1
abrine	increases expression	1
nilotinib	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Dabigatran	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5323277	Binding	Induction of FOXC2 degradation in human PC-3 cells assessed as decrease in FOXC2 protein level at 20 uM incubated for 48 hrs by Western blot analysis	A FOXC2 inhibitor, MC-1-F2, as a therapeutic candidate for targeting EMT in castration-resistant prostate cancer. — Bioorg Med Chem Lett

Cellosaurus cell lines

8 cell lines: 4 cancer cell line, 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1X4	SEES3-1V human FOXC2, clone1	Embryonic stem cell	Male
CVCL_A1X5	SEES3-1V human FOXC2, clone2	Embryonic stem cell	Male
CVCL_A1X6	SEES3-1V human FOXC2, clone3	Embryonic stem cell	Male
CVCL_B8GE	Abcam HCT 116 FOXC2 KO	Cancer cell line	Male
CVCL_B9IN	Abcam A-549 FOXC2 KO	Cancer cell line	Male
CVCL_D1SK	Abcam U-87MG FOXC2 KO	Cancer cell line	Male
CVCL_D2F8	Abcam MCF-7 FOXC2 KO	Cancer cell line	Female
CVCL_DQ94	LDS-iPSC8	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04308603	Not specified	COMPLETED	Multicentric Prospective Study to Screen Inborn Errors of Metabolism in Non-immune Hydrops (NIH) Fetalis by Massively Parallel Sequencing
NCT05528796	Not specified	ENROLLING_BY_INVITATION	Uncovering the Etiologies of Non-immune Hydrops Fetalis