FOXF1

Summary

FOXF1 (forkhead box F1, HGNC:3809) is a protein-coding gene on chromosome 16q24.1, encoding Forkhead box protein F1 (Q12946). Probable transcription activator for a number of lung-specific genes. It is haploinsufficient (ClinGen: sufficient evidence).

This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the regulation of pulmonary genes as well as embryonic development.

Source: NCBI Gene 2294 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alveolar capillary dysplasia with misalignment of pulmonary veins (Definitive, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 245 total — 46 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 75
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3809
Approved symbol	FOXF1
Name	forkhead box F1
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	FREAC1
Ensembl gene	ENSG00000103241
Ensembl biotype	protein_coding
OMIM	601089
Entrez	2294

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000262426

RefSeq mRNA: 1 — MANE Select: NM_001451 NM_001451

CCDS: CCDS10957

Canonical transcript exons

ENST00000262426 — 2 exons

Exon	Start	End
ENSE00001121720	86512925	86515422
ENSE00001286040	86510527	86511548

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 94.60.

FANTOM5 (CAGE): breadth broad, TPM avg 6.8378 / max 355.5203, expressed in 650 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155443	6.8378	650

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	94.60	gold quality
mucosa of stomach	UBERON:0001199	94.38	gold quality
right lung	UBERON:0002167	94.15	gold quality
lower lobe of lung	UBERON:0008949	93.84	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.43	gold quality
lower esophagus	UBERON:0013473	93.39	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.22	gold quality
urinary bladder	UBERON:0001255	92.77	gold quality
sigmoid colon	UBERON:0001159	92.45	gold quality
mucosa of urinary bladder	UBERON:0001259	90.83	gold quality
buccal mucosa cell	CL:0002336	90.75	silver quality
upper lobe of lung	UBERON:0008948	89.71	gold quality
upper lobe of left lung	UBERON:0008952	89.58	gold quality
lung	UBERON:0002048	88.45	gold quality
pylorus	UBERON:0001166	88.25	gold quality
fundus of stomach	UBERON:0001160	88.24	gold quality
colon	UBERON:0001155	87.95	gold quality
large intestine	UBERON:0000059	87.69	gold quality
urethra	UBERON:0000057	87.55	gold quality
cardia of stomach	UBERON:0001162	87.33	gold quality
prostate gland	UBERON:0002367	87.11	gold quality
intestine	UBERON:0000160	86.47	gold quality
transverse colon	UBERON:0001157	86.38	gold quality
gall bladder	UBERON:0002110	85.29	gold quality
lower esophagus mucosa	UBERON:0035834	85.05	gold quality
colonic epithelium	UBERON:0000397	84.94	gold quality
body of stomach	UBERON:0001161	84.33	gold quality
stomach	UBERON:0000945	84.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.93	gold quality
periodontal ligament	UBERON:0008266	83.92	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	41.45
E-ANND-3	yes	15.38
E-MTAB-9388	yes	13.94
E-MTAB-7249	yes	6.90
E-GEOD-83139	yes	6.72

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
CDH1	Unknown
FGF2	Unknown
GH2	Activation
HGF	Unknown
ITGB3	Activation
MYLK	Unknown
SCGB1A1	Activation
SELP	Activation

Upstream regulators (CollecTRI, top): FOXA2, FOXC1, FOXM1, GLI2, GLI3, HOXA13

miRNA regulators (miRDB)

114 targeting FOXF1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-12118	100.00	65.88	1270
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• A pattern of strong Shh expression with weak expression of Foxf1 in all cases of UIP (usual interstitial pneumonitis) and a complementary expression of Shh and Foxf1 in cases of nonspecific interstitial pneumonitis (NSIP-F). (PMID:16448649)
• FOXF1 induces growth hormone variant expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter (PMID:16772323)
• Inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. (PMID:19500772)
• A role for FOXF1 in esophageal atresia, tracheoesophageal fistula and the VACTERL association is presented. (PMID:19822228)
• FoxF1 was found to be a direct repressed target of NF1-C2; first evidence for a role of FoxF1 in cancer and regulation of EMT; overexpression associated with mesenchymal phenotype, increased invasiveness and enhanced growth of breast carcinoma xenografts (PMID:20145151)
• Observations suggest that hedgehog-dependent FoxF1 is a clinically relevant lung CAF-inducing factor, and support experimentally the general concept that CAF properties can be induced by activation of developmentally important transcription factors. (PMID:20233876)
• Recognition of a specific syndrome is possible, one of several examples discussed being the recently described association of intestinal malrotation with alveolar capillary dysplasia, due to mutations in the forkhead box transcription factor FOXF1. (PMID:20549505)
• FOFOXF1 was highly expressed in metastatic rhabdomyosarcoma, alveolar tumor samples and with a significant lower expression in non-metastatic samples (PMID:21271214)
• Results from mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX gene cluster on chromosome 16q24 in the studied patients. (PMID:21315191)
• FOXF1 expression is predominantly silenced in breast and colorectal cancer cell lines with inactive p53 (PMID:21964066)
• Deletions in the regulatory sequence of maternally inherited FOXF1 were identified in patients with persistent fetal circulation syndrome. (PMID:23034409)
• findings show FOXF1 is frequently overexpressed in colorectal tumor epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts; identified that overexpressed FOXF1 proteins are mislocalized in the cytoplasm of tumor epithelial cells, which positively correlates with poor prognostic factors of colorectal cancer (PMID:23103611)
• Case Report: heterozygous nonsense mutation c.539C>A;p.S180X in the first exon of FOXF1, in a patient with alveolar capillary dysplasia with misalignment of pulmonary veins associated with annular pancreas and intestinal malrotation. (PMID:23407133)
• this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett’s esophagus, also increase esophageal carcinoma and esophageal adenocarcinoma susceptibility in Caucasians (PMID:23504527)
• We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis. (PMID:23505205)
• Bmi1 and FoxF1 may cooperate with hedgehog signaling in non-small-cell lung carcinogenesis. (PMID:23864317)
• Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins. (PMID:23943206)
• FOXF1 and p53 form a portion of a regulatory transcriptional network that appears to have an important role in cancer cell invasion and migration. (PMID:24186199)
• we narrowed the regulatory region located ~272 kb upstream to FOXF1 to ~60 kb and showed that its loss correlated with a decrease of FOXF1 expression in vivo. (PMID:24842713)
• FOXF1 behaved not only as a reprogramming regulator that mediates stemness but also as a putative tumor suppressor that contributes to p21-regulated growth suppression during fusion process (PMID:25237908)
• FOXF1 was induced by the antifibrotic mediator Prostaglandin E2 and repressed by the profibrotic cytokine TGF-beta1, and FOXF1 repressed cell growth and collagen-1 expression in normal lung fibroblasts, consistent with participation in antifibrotic pathways. (PMID:25260753)
• Data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. (PMID:25472632)
• FOXF1 inhibits hematopoietic lineage commitment during early mesoderm specification. (PMID:26293303)
• Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association (PMID:26294094)
• we provide supportive evidence that genetic variants at FOXP1, BARX1, and FOXF1 confer risk for the development of EAC. (PMID:26383589)
• Single-nucleotide polymorphisms FOXF1 rs9936833 and MHC rs9257809 remained significantly associated with presence of gastroesophageal acid reflux. The association for risk allele C in FOXF1 rs9936833 and risk allele A in MHC rs9257809 with the presence of acid reflux suggests a potential pathophysiologic mechanism for the role of genetic influences in Barret Esophagus development. (PMID:26822871)
• Results show that FoxF1 increases invasiveness of breast cancer cells by upregulating LOX. (PMID:26908052)
• Point mutations of FOXF1 gene is associated with alveolar capillary dysplasia. (PMID:27071622)
• reported the first familial case of ACDMVP as a result of maternal somatic mosaic FOXF! mutation, which provided additional evidence for this novel imprinting disorder (PMID:27109257)
• FOXF1 mutations may have an extremely variable phenotype, possibly as a result of somatic mosaicism and complex gene regulation. (PMID:27145217)
• the R139Q substitution in FOXF1 causes infantile hypertrophic pyloric stenosis in a family and implies a novel pathological pathway for the condition (PMID:27855150)
• There were decreased levels of Gsa, FOXF1, CREB1, and phosphorylated CREB1 proteins in intestinal muscle layers of patients with chronic intestinal pseudo-obstruction, compared with tissues from controls. (PMID:28043906)
• Data show that MeCP2 promotes gastric cancer (GC) cell proliferation via FOXF1-mediated Wnt5a/beta-Catenin signaling pathway, and suppresses GC cell apoptosis through MYOD1-mediated Caspase-3 signaling pathway. (PMID:28131747)
• we describe monozygotic twins and one full-term newborn with ACD and gastrointestinal malformations caused by de novo mutations of FOXF1 on the maternal-inherited alleles. (PMID:28256047)
• FOXF1 rs3950627 was significantly associated with survival in gastric cancer patients from two populations; Japan and California. (PMID:28398355)
• gene polymorphism is associated with increased colorectal cancer risk in the Han Chinese population (PMID:28404937)
• our data indicate that FOXF1 represents not only a novel diagnostic biomarker, but also a potential novel therapeutic target in GIST. (PMID:29162563)
• Mutations in SFTPC, NKX2.1, and FOXF1 were identified among Japanese infants and children with childhood interstitial lung disease, whereas ABCA3 mutations were rare. (PMID:29569581)
• the varients of FOXP1 and FOXF1 genes are functionally associated with oesophageal adenocarcinoma in Chinese population. (PMID:29666340)
• circNASP contributes to malignant behaviors of osteosarcoma cells by miR-1253/FOXF1 pathway. (PMID:29678578)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxf1	ENSDARG00000015399
mus_musculus	Foxf1	ENSMUSG00000042812
rattus_norvegicus	Foxf1	ENSRNOG00000049906

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), 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), FOXC2 (ENSG00000176692), 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 F1 — Q12946 (reviewed: Q12946)

Alternative names: Forkhead-related activator 1, Forkhead-related protein FKHL5, Forkhead-related transcription factor 1

All UniProt accessions (1): Q12946

UniProt curated annotations — full annotation on UniProt →

Function. Probable transcription activator for a number of lung-specific genes.

Subcellular location. Nucleus.

Tissue specificity. Expressed in lung and placenta.

Disease relevance. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) [MIM:265380] A rare developmental disorder characterized by abnormal development of the capillary vascular system in the lungs. Histological features include failure of formation and ingrowth of alveolar capillaries, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. Affected infants present with respiratory distress and the disease is fatal within the newborn period. Additional features include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs. ACDMPV is a rare cause of persistent pulmonary hypertension of the newborn, an abnormal physiologic state caused by failure of transition of the pulmonary circulation from the high pulmonary vascular resistance of the fetus to the low pulmonary vascular resistance of the newborn. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Activation domains C-terminal of (and distinct from) the forkhead domains are necessary for transcriptional activation.

RefSeq proteins (1): NP_001442* (*=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
IPR051770	Forkhead_box_regulator	Family

Pfam: PF00250

UniProt features (26 total): sequence variant 22, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12946-F1	59.41	0.21

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9758920	Formation of lateral plate mesoderm
R-HSA-9762293	Regulation of CDH11 gene transcription

MSigDB gene sets: 457 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, BENPORATH_ES_WITH_H3K27ME3, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS, PID_HNF3B_PATHWAY, GOBP_INFLAMMATORY_RESPONSE, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_ESTABLISHMENT_OF_EPITHELIAL_CELL_POLARITY

GO Biological Process (52): negative regulation of transcription by RNA polymerase II (GO:0000122), blood vessel development (GO:0001568), vasculogenesis (GO:0001570), in utero embryonic development (GO:0001701), somitogenesis (GO:0001756), morphogenesis of a branching structure (GO:0001763), positive regulation of mesenchymal cell proliferation (GO:0002053), endocardial cushion development (GO:0003197), cardiac left ventricle morphogenesis (GO:0003214), regulation of transcription by RNA polymerase II (GO:0006357), smoothened signaling pathway (GO:0007224), determination of left/right symmetry (GO:0007368), midgut development (GO:0007494), heart development (GO:0007507), animal organ morphogenesis (GO:0009887), positive regulation of cell-substrate adhesion (GO:0010811), detection of wounding (GO:0014822), extracellular matrix organization (GO:0030198), respiratory tube development (GO:0030323), lung development (GO:0030324), positive regulation of cell migration (GO:0030335), pancreas development (GO:0031016), negative regulation of mast cell degranulation (GO:0043305), establishment of epithelial cell apical/basal polarity (GO:0045198), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), lung alveolus development (GO:0048286), lateral mesodermal cell differentiation (GO:0048371), embryonic digestive tract morphogenesis (GO:0048557), digestive tract development (GO:0048565), embryonic ectodermal digestive tract morphogenesis (GO:0048613), embryonic foregut morphogenesis (GO:0048617), negative regulation of inflammatory response (GO:0050728), smooth muscle cell differentiation (GO:0051145), lung vasculature development (GO:0060426), trachea development (GO:0060438), epithelial tube branching involved in lung morphogenesis (GO:0060441), right lung morphogenesis (GO:0060461), lung lobe morphogenesis (GO:0060463), venous blood vessel development (GO:0060841)

GO Molecular Function (8): 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, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565), transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gastrulation	1
Regulation of CDH11 Expression and Function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	4
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
chordate embryonic development	2
anatomical structure morphogenesis	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
vasculature development	1
anatomical structure development	1
cell differentiation	1
blood vessel morphogenesis	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
multicellular organismal process	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
heart development	1
mesenchyme development	1
cardiac ventricle morphogenesis	1
cell surface receptor signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
digestive tract development	1
circulatory system development	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
positive regulation of cell adhesion	1
detection of external stimulus	1
response to wounding	1
extracellular structure organization	1
external encapsulating structure organization	1
tube development	1
respiratory tube development	1
respiratory system development	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

1630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXF1	GLI3	P10071	822
FOXF1	SFTPB	P07988	746
FOXF1	CPS1	P31327	719
FOXF1	GLI2	P10070	715
FOXF1	GLI1	P08151	690
FOXF1	SHH	Q15465	676
FOXF1	MYOCD	Q8IZQ8	636
FOXF1	ZIC3	O60481	620
FOXF1	BARX1	Q9HBU1	602
FOXF1	SRF	P11831	575
FOXF1	BMP4	P12644	552
FOXF1	RELA	Q04206	552
FOXF1	SCGB1A1	P11684	550
FOXF1	MTHFSD	Q2M296	550
FOXF1	FGF2	P09038	548

IntAct

23 interactions, top by confidence:

A	B	Type	Score
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530
IFNA1	FOXF1	psi-mi:“MI:0915”(physical association)	0.370
	FOXF1	psi-mi:“MI:0915”(physical association)	0.370
FOXF1	HOXB9	psi-mi:“MI:0914”(association)	0.350
FOXF1	CPS1	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
ICAM1	RTL8C	psi-mi:“MI:0914”(association)	0.350
PRG2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
FBLN5	ZNF320	psi-mi:“MI:0914”(association)	0.350
FOXF2	VWA8	psi-mi:“MI:0914”(association)	0.350
CPA5	RAP1BL	psi-mi:“MI:0914”(association)	0.350
MAGEA8	METTL15	psi-mi:“MI:0914”(association)	0.350
ICAM1	TUBB8B	psi-mi:“MI:0914”(association)	0.350
DKK3	MYO9A	psi-mi:“MI:0914”(association)	0.350
PRSS50	PRSS46P	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
FOXF1	PPP2R5D	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): FOXF1 (Affinity Capture-MS), FOXF1 (Affinity Capture-MS), SATB1 (Affinity Capture-MS), FUBP3 (Affinity Capture-MS), HOXD13 (Affinity Capture-MS), SATB2 (Affinity Capture-MS), HOXB13 (Affinity Capture-MS), HOXB9 (Affinity Capture-MS), STRBP (Affinity Capture-MS), FOXF1 (Affinity Capture-MS), GAPVD1 (Affinity Capture-MS), KHSRP (Affinity Capture-MS), CPS1 (Affinity Capture-MS), FLNC (Affinity Capture-MS), PUSL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8V0YY16, A0JPN1, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A2T7J2, A3KNJ3, A7MB54, A8MTJ6, B5RHS5, D3Z120, O54743, P09027, P14653, P17919, P31249, P32183, P35584, P55316, P55318, P56260, Q00939, Q12946, Q12947, Q12948, Q12951, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28D67, Q28HT3, 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

2 interactions.

A	Effect	B	Mechanism
FOXF1	“up-regulates quantity by expression”	GH2	“transcriptional regulation”
GLI2	“up-regulates quantity by expression”	FOXF1	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	19
Uncertain significance	95
Likely benign	39
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030400	NM_001451.3(FOXF1):c.668C>A (p.Ser223Ter)	Pathogenic
1300142	NM_001451.3(FOXF1):c.276G>A (p.Trp92Ter)	Pathogenic
1302014	NM_001451.3(FOXF1):c.852_856del (p.Tyr284_Lys286delinsTer)	Pathogenic
1322932	NM_001451.3(FOXF1):c.889del (p.Ala297fs)	Pathogenic
1448136	NM_001451.3(FOXF1):c.121dup (p.Ala41fs)	Pathogenic
1708313	NM_001451.3(FOXF1):c.260dup (p.Ser88fs)	Pathogenic
1710679	NM_001451.3(FOXF1):c.257G>C (p.Arg86Pro)	Pathogenic
228348	NM_001451.2(FOXF1):c.(?15)(*58_?)del	Pathogenic
2500699	NM_001451.3(FOXF1):c.21del (p.Lys7fs)	Pathogenic
2505284	NM_001451.3(FOXF1):c.1070_1080del (p.His357fs)	Pathogenic
2584476	NM_001451.3(FOXF1):c.797C>A (p.Ser266Ter)	Pathogenic
2584540	NM_001451.3(FOXF1):c.185A>C (p.Gln62Pro)	Pathogenic
2635136	NM_001451.3(FOXF1):c.310G>T (p.Glu104Ter)	Pathogenic
2662961	NM_001451.3(FOXF1):c.268C>T (p.Gln90Ter)	Pathogenic
2814525	NM_001451.3(FOXF1):c.442del (p.Cys148fs)	Pathogenic
3235920	NM_001451.3(FOXF1):c.802_805del (p.Ala268fs)	Pathogenic
3238755	NM_001451.3(FOXF1):c.1138T>A (p.Ter380Arg)	Pathogenic
3256575	NM_001451.3(FOXF1):c.229T>C (p.Phe77Leu)	Pathogenic
3899466	NM_001451.3(FOXF1):c.246C>A (p.Phe82Leu)	Pathogenic
4279919	NM_001451.3(FOXF1):c.385G>T (p.Glu129Ter)	Pathogenic
4531621	NM_001451.3(FOXF1):c.225C>G (p.Tyr75Ter)	Pathogenic
4540015	NM_001451.3(FOXF1):c.363C>G (p.Tyr121Ter)	Pathogenic
4755386	NM_001451.3(FOXF1):c.245_246insA (p.Phe82fs)	Pathogenic
692054	NM_001451.3(FOXF1):c.691_698del (p.Ala231fs)	Pathogenic
800364	NM_001451.3(FOXF1):c.1031_1032del (p.Phe344fs)	Pathogenic
800365	NM_001451.3(FOXF1):c.145C>T (p.Pro49Ser)	Pathogenic
800366	NM_001451.3(FOXF1):c.89C>A (p.Ser30Ter)	Pathogenic
800367	NM_001451.3(FOXF1):c.872_879del (p.Leu290_Ser291insTer)	Pathogenic
800368	NM_001451.3(FOXF1):c.899_903dup (p.Gly302fs)	Pathogenic
800369	NM_001451.3(FOXF1):c.191C>A (p.Ser64Ter)	Pathogenic

SpliceAI

383 predictions. Top by Δscore:

Variant	Effect	Δscore
16:86511545:CAAGG:C	donor_loss	1.0000
16:86511546:AAGGT:A	donor_loss	1.0000
16:86511547:AGGTG:A	donor_loss	1.0000
16:86511548:GGTG:G	donor_loss	1.0000
16:86511549:G:C	donor_loss	1.0000
16:86511550:T:A	donor_loss	1.0000
16:86512923:A:AG	acceptor_gain	1.0000
16:86512924:G:GG	acceptor_gain	1.0000
16:86511544:GCAAG:G	donor_gain	0.9900
16:86511549:G:GG	donor_gain	0.9900
16:86512920:TGCA:T	acceptor_loss	0.9900
16:86512921:GCA:G	acceptor_loss	0.9900
16:86512922:CA:C	acceptor_loss	0.9900
16:86512923:A:AC	acceptor_loss	0.9900
16:86512924:GGC:G	acceptor_gain	0.9900
16:86511547:AG:A	donor_gain	0.9800
16:86511548:GG:G	donor_gain	0.9800
16:86512910:C:A	acceptor_gain	0.9800
16:86512923:AG:A	acceptor_gain	0.9800
16:86512924:GG:G	acceptor_gain	0.9800
16:86512924:GGCAT:G	acceptor_gain	0.9800
16:86512990:A:AG	acceptor_gain	0.9800
16:86512991:A:G	acceptor_gain	0.9700
16:86512907:T:A	acceptor_gain	0.9600
16:86515210:A:AG	acceptor_gain	0.9600
16:86515211:G:GG	acceptor_gain	0.9600
16:86512915:C:CA	acceptor_gain	0.9500
16:86512924:GGCA:G	acceptor_gain	0.9500
16:86512990:AAC:A	acceptor_gain	0.9500
16:86512992:C:CA	acceptor_gain	0.9500

AlphaMissense

2467 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:86510702:C:A	R45S	1.000
16:86510711:A:C	K48Q	1.000
16:86510711:A:G	K48E	1.000
16:86510712:A:T	K48M	1.000
16:86510713:G:C	K48N	1.000
16:86510713:G:T	K48N	1.000
16:86510714:C:A	P49T	1.000
16:86510714:C:T	P49S	1.000
16:86510715:C:A	P49Q	1.000
16:86510715:C:G	P49R	1.000
16:86510720:T:G	Y51D	1.000
16:86510723:T:C	S52P	1.000
16:86510724:C:A	S52Y	1.000
16:86510724:C:G	S52C	1.000
16:86510724:C:T	S52F	1.000
16:86510726:T:C	Y53H	1.000
16:86510727:A:G	Y53C	1.000
16:86510729:A:T	I54F	1.000
16:86510730:T:A	I54N	1.000
16:86510730:T:C	I54T	1.000
16:86510730:T:G	I54S	1.000
16:86510732:G:C	A55P	1.000
16:86510733:C:A	A55E	1.000
16:86510733:C:T	A55V	1.000
16:86510735:C:T	L56F	1.000
16:86510736:T:A	L56H	1.000
16:86510736:T:C	L56P	1.000
16:86510736:T:G	L56R	1.000
16:86510738:A:T	I57F	1.000
16:86510739:T:A	I57N	1.000

dbSNP variants (sampled 300 via entrez): RS1000373439 (16:86515908 G>C), RS1000705848 (16:86514925 C>G), RS1000882881 (16:86511463 C>A,T), RS1000913775 (16:86511143 C>G,T), RS1001110161 (16:86515344 C>G,T), RS1001280331 (16:86515655 C>T), RS1001319774 (16:86511865 A>C), RS1001649756 (16:86515868 C>T), RS1001689004 (16:86511643 C>A,T), RS1001708326 (16:86515477 C>G,T), RS1001730944 (16:86515282 T>A), RS1002056707 (16:86514197 A>G,T), RS1002431933 (16:86511726 C>G), RS1002806436 (16:86514480 T>C), RS1002958199 (16:86510479 T>G)

Disease associations

OMIM: gene MIM:601089 | disease phenotypes: MIM:265380, MIM:612525, MIM:192350, MIM:614429, MIM:601894

GenCC curated gene-disease

Disease	Classification	Inheritance
alveolar capillary dysplasia with misalignment of pulmonary veins	Definitive	Autosomal dominant

Mondo (6): alveolar capillary dysplasia with misalignment of pulmonary veins (MONDO:0009934), pyloric stenosis, infantile hypertrophic, 5 (MONDO:0012922), VACTERL/vater association (MONDO:0008642), ventricular septal defect (MONDO:0002070), atresia of urethra (MONDO:0015195), glomerulopathy with fibronectin deposits 2 (MONDO:0011165)

Orphanet (6): Congenital alveolar capillary dysplasia (Orphanet:210122), VACTERL/VATER association (Orphanet:887), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Atresia of urethra (Orphanet:105), Fibronectin glomerulopathy (Orphanet:84090), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000248	Brachycephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000490	Deeply set eye
HP:0000813	Bicornuate uterus
HP:0000913	Posterior rib fusion
HP:0001195	Single umbilical artery
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001539	Omphalocele
HP:0001540	Diastasis recti
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001636	Tetralogy of Fallot
HP:0001643	Patent ductus arteriosus
HP:0001647	Bicuspid aortic valve
HP:0001650	Aortic valve stenosis
HP:0001655	Patent foramen ovale
HP:0001667	Right ventricular hypertrophy
HP:0001680	Coarctation of aorta

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001675_5	Barrett’s esophagus	3.000000e-10
GCST001819_7	Corneal astigmatism	2.000000e-06
GCST001957_18	Obesity (early onset extreme)	6.000000e-06
GCST002231_7	Digestive system disease (Barrett’s esophagus and esophageal adenocarcinoma combined)	1.000000e-06
GCST002232_7	Esophageal adenocarcinoma	4.000000e-06
GCST002727_1	Breast cancer (survival)	6.000000e-06
GCST003740_13	Barrett’s esophagus or Esophageal adenocarcinoma	3.000000e-08
GCST006628_44	Systolic blood pressure	5.000000e-10
GCST009356_16	Nonsyndromic cleft palate	2.000000e-08
GCST010244_121	Triglyceride levels	1.000000e-08
GCST90011899_156	Aspartate aminotransferase levels	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time
EFO:0006335	systolic blood pressure
EFO:0004530	triglyceride measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
C536590	Alveolar capillary dysplasia (supp.)
C567283	Pyloric Stenosis, Infantile Hypertrophic, 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
bisphenol A	increases expression, increases methylation	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	2
Cadmium	decreases expression, increases abundance	2
Aflatoxin B1	affects expression, increases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
ferrous chloride	decreases expression	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Troglitazone	increases expression	1
Arsenic	increases methylation	1
Catechin	affects cotreatment, increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Triclosan	increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases abundance, decreases expression	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1Z7	SEES3-1V human FOXF1, clone1	Embryonic stem cell	Male
CVCL_A1Z8	SEES3-1V human FOXF1, clone2	Embryonic stem cell	Male
CVCL_A1Z9	SEES3-1V human FOXF1, clone3	Embryonic stem cell	Male
CVCL_YZ93	EMCi127-A	Induced pluripotent stem cell	Male
CVCL_YZ94	EMCi127-B	Induced pluripotent stem cell	Male
CVCL_YZ95	EMCi128-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00732537	PHASE4	COMPLETED	Inhaled Nitric Oxide by Oxygen Hood in Neonates
NCT02914652	PHASE4	COMPLETED	The Cardiopulmonary Effect of Inhaled Beta-2-agonists on Adult Patients Born With Ventricular Septum Defects.
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00113698	PHASE3	TERMINATED	Angiotensin Converting Enzyme Inhibition in Children With Mitral Regurgitation
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT00556361	PHASE2	COMPLETED	Use of Ketamine Prior to Cardiopulmonary Bypass in Children
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT04017975	PHASE2	ACTIVE_NOT_RECRUITING	Optical Tissue Identification for Myocardial Architecture
NCT01825369	PHASE1	WITHDRAWN	Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT04328636	PHASE1/PHASE2	COMPLETED	Nebulized MgSO4 in Persistent Pulmonary Hypertension of Newborn
NCT03799705	Not specified	COMPLETED	Genetic Variants in Nicotinamide Adenine Dinucleotide (NAD) Synthesis Pathway
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT06298344	EARLY_PHASE1	COMPLETED	The Role of Thiamine After Transcatheter Closure in Children With Left-to-Right Shunt Congenital Heart Disease
NCT00005190	Not specified	COMPLETED	Reproduction and Survival After Cardiac Defect Repair
NCT00005322	Not specified	COMPLETED	Molecular Genetic Epidemiology of Endocardial Cushion Defects - SCOR in Pediatric Cardiovascular Disease
NCT00005546	Not specified	COMPLETED	Molecular Genetic Epidemiology of Three Cardiac Defects -SCOR in Pediatric Cardiovascular Disease
NCT00006272	Not specified	UNKNOWN	Study of Energy Expenditure in Infants With Ventricular Septal Defects
NCT00173186	Not specified	UNKNOWN	Aortic Regurgitation After Surgical Repair of Outlet-Type Ventricular Septal Defect
NCT00229827	Not specified	TERMINATED	Optimal Timing for Repair of Left to Right Shunt Lesions
NCT00390702	Not specified	COMPLETED	Safety and Effectiveness of the Nit-Occlud® Lê VSD Spiral Coil System
NCT00583505	Not specified	NO_LONGER_AVAILABLE	Emergency/Compassionate Use - Membranous VSD Occluder
NCT00583791	Not specified	COMPLETED	Closure of Muscular Ventricular Septal Defects With The AMPLATZER™ Muscular VSD Occluder
NCT00590382	Not specified	APPROVED_FOR_MARKETING	Emergency/Compassionate Use - Muscular VSD Occluder
NCT00647387	Not specified	COMPLETED	Closure of Muscular Ventricular Septal Defects (VSDs) With the AMPLATZER Muscular VSD (MuVSD) Occluder - Post Approval Study
NCT00890799	Not specified	COMPLETED	Transcatheter Closure Versus Surgery of Perimembranous Ventricular Septal Defects
NCT01313832	Not specified	COMPLETED	The Effect of Remote Ischemic Preconditioning on the Ischemic Reperfusion Injury in Infants With Ventricular Septal Defect and Pulmonary Hypertension
NCT01480908	Not specified	COMPLETED	Right Bundle Branch Block After Surgical Closure of Ventricular Septal Defect
NCT02138435	Not specified	COMPLETED	Longterm Outcome After Ventricular Septal Defect Closure
NCT02361008	Not specified	COMPLETED	A Randomized Controlled Trial:Treatments on Infundibular Ventricular Septal Defect
NCT02552485	Not specified	COMPLETED	Evaluation of Latent Pulmonary Arterial Hypertension in Congenital Shunt Lesions
NCT03127748	Not specified	UNKNOWN	Cardiac Function After Transcatheter VSD Closure
NCT03684161	Not specified	COMPLETED	Cardiopulmonary Function in Adults Born With a Ventricular Septal Defect
NCT03941691	Not specified	UNKNOWN	A Trial to Evaluate the Safety and Efficacy of a Fully Degradable Ventricular Septal Defect (VSD) Closure
NCT04417712	Not specified	COMPLETED	Lifetech KONAR MFO Post-Market Clinical Follow-Up Study
NCT04667455	Not specified	COMPLETED	Improving Care for Children With Congenital Heart Disease.
NCT04859036	Not specified	COMPLETED	The Effect of Transcatheter Ventricular Septal Defect Closure on Heart Rate Variability Parameters
NCT05200910	Not specified	COMPLETED	The Effect of Transcatheter VSD Closure on Children’s Appetite, Hormones and Growth