FOXL2

Summary

FOXL2 (forkhead box L2, HGNC:1092) is a protein-coding gene on chromosome 3q22.3, encoding Forkhead box protein L2 (P58012). Transcriptional regulator. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3.

Source: NCBI Gene 668 — RefSeq curated summary.

At a glance

• Gene–disease (curated): blepharophimosis, ptosis, and epicanthus inversus syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 305 total — 131 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 49
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 44 downstream targets (CollecTRI)
• MANE Select transcript: NM_023067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1092
Approved symbol	FOXL2
Name	forkhead box L2
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Aliases	BPES1
Ensembl gene	ENSG00000183770
Ensembl biotype	protein_coding
OMIM	605597
Entrez	668

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000648323

RefSeq mRNA: 1 — MANE Select: NM_023067 NM_023067

CCDS: CCDS3105

Canonical transcript exons

ENST00000648323 — 1 exons

Exon	Start	End
ENSE00003835336	138944224	138947137

Expression profiles

Bgee: expression breadth broad, 84 present calls, max score 89.40.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9581 / max 81.4795, expressed in 415 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44777	0.8759	301
44778	0.7032	270
44776	0.1009	44
44773	0.0757	30
44775	0.0728	31
44774	0.0557	22
44772	0.0542	13
44771	0.0196	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	89.40	gold quality
stromal cell of endometrium	CL:0002255	88.31	gold quality
ovary	UBERON:0000992	86.53	gold quality
right ovary	UBERON:0002118	85.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.82	gold quality
endocervix	UBERON:0000458	80.69	gold quality
decidua	UBERON:0002450	79.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.96	gold quality
left uterine tube	UBERON:0001303	77.94	gold quality
pituitary gland	UBERON:0000007	76.49	gold quality
endometrium	UBERON:0001295	75.98	gold quality
right uterine tube	UBERON:0001302	74.21	gold quality
adenohypophysis	UBERON:0002196	73.44	gold quality
uterus	UBERON:0000995	71.39	gold quality
ectocervix	UBERON:0012249	71.29	gold quality
female reproductive system	UBERON:0000474	70.70	gold quality
body of uterus	UBERON:0009853	68.54	gold quality
uterine cervix	UBERON:0000002	67.93	gold quality
myometrium	UBERON:0001296	66.62	gold quality
right adrenal gland cortex	UBERON:0035827	66.56	gold quality
fallopian tube	UBERON:0003889	65.70	gold quality
right adrenal gland	UBERON:0001233	65.43	gold quality
left adrenal gland	UBERON:0001234	64.43	gold quality
left adrenal gland cortex	UBERON:0035825	63.30	gold quality
adrenal cortex	UBERON:0001235	63.22	gold quality
germinal epithelium of ovary	UBERON:0001304	61.02	gold quality
adrenal gland	UBERON:0002369	60.93	gold quality
vagina	UBERON:0000996	60.53	gold quality
oviduct epithelium	UBERON:0004804	58.86	silver quality
mammalian vulva	UBERON:0000997	56.96	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.25

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

44 targets.

Target	Regulation
ACTA2
AMH	Unknown
ATF3	Unknown
BCL2A1	Unknown
CCL20	Unknown
CCL3	Unknown
CCL3L1	Unknown
CCND2	Repression
CGA	Activation
CH25H	Unknown
CLU	Unknown
CXCL2	Unknown
CXCL3	Unknown
CYP11A1	Repression
CYP11B2
CYP17A1	Repression
CYP19A1	Repression
CYP26B1	Unknown
CYP2B6
DLST
DMRT1
FOS	Unknown
FSHB	Unknown
FST	Unknown
GFM1
GNRHR	Activation
IER3	Unknown
IFNL1	Unknown
IL11	Unknown
INHBA

Upstream regulators (CollecTRI, top): LHX3, LHX4, NR5A1, TCF3

miRNA regulators (miRDB)

64 targeting FOXL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22 (PMID:11474656)
• Insertion of cytosine in FOXL2 gene is associated with blepharophimosis (PMID:11910558)
• Two novel frameshift mutations of FOXL2 described in Blepharophimosis/ptosis/epicanthus inversus syndrome (PMID:11960581)
• Two novel mutations in FOXL2 are associated with premature ovarian failure. (PMID:12149404)
• In patients with premature ovarian failure as well as in XX males lacking the testis-determining gene SRY, seven novel FOXL2 variations have been described. (PMID:12161610)
• Molecular evolution and expression of FOXL2 (PMID:12471206)
• Two mutational hotspots are described and are associated with blepharophimosis syndrome. (PMID:12529855)
• Five novel mutations in Bleparophimosis ptosis epicanthus inversus syndrome patients (PMID:12938087)
• conserved sequences are candidates for models in which they are distant enhancers or otherwise affect higher order chromatin structure to impose long-range cis regulation of FOXL2 expression (PMID:15081106)
• Results indicate that mutations in the FOXL2 coding region are rarely associated with non-syndromic premature ovarian failure. (PMID:15181179)
• This study reports for the first time a novel missense mutation in a five-generation Indian family with BPES (Blepharophimosis-ptosis-epicanthus inversus syndrome). (PMID:15257268)
• The Human FOXL2 Mutation Database provides a publicly available online resource about FOXL2 mutations/variants associated with BPES syndrome & premature ovarian failure. It allows remote users to submit new mutations and to query the database online. (PMID:15300845)
• the mechanism for the molecular pathogenesis of the polyAla expansions of FOXL2 may be its mislocalisation concomitant with its inclusion into nuclear aggregates (PMID:15591279)
• analysis of extragenic deletions in blepharophimosis syndrome and evidence of potential long-range cis-regulatory elements regulating FOXL2 expression (PMID:15962237)
• Findings indicated that the 951-953(delC) deletion mutation in the FOXL2 gene in the two patients resulted in truncated proteins and hence led to their blepharophimosis, ptosis, and epicanthus inversus syndrome. (PMID:16086270)
• FOXL2 mutation 904_939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst. (PMID:16131596)
• A complete deletion of the polyAla tract of FOXL2 induces a significant intranuclear aggregation. (PMID:16219626)
• Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation. (PMID:16283882)
• Gene rearrangements in FOXL2 is associated with Blepharophimosis-ptosis-epicanthus inversus syndrome (PMID:16394030)
• The mutations causing Blepharophimosis-ptosis-epicanthus inversus syndrome are found in the FOXL2 gene, a forkhead transcription factor, located in 3q23. (PMID:16814186)
• Mutant 5-residue polyalanine expansion of FoxL2 leads to recessive inheritance of blepharophimosis syndrome associated with ovarian dysfunction. (PMID:17089161)
• Our results expand the spectrum of FOXL2 mutations and confirm the mutation hotspot in FOXL2. (PMID:17277738)
• A 892C > T mutation in FOXL2 was found in patients with blepharophimosis-ptosis-epicanthus inversus syndrome. (PMID:17393695)
• The 901 - 930 dup 30 mutation of FOXL2 causes great changes in the primary and secondary structure, which may be the molecular pathogenesis of blepharophimosis-ptosis-epicanthus inversus syndrome. (PMID:17897532)
• FOXL2 mutations in Indian families with blepharophimosis-ptosis-epicanthus inversus syndrome. (PMID:17968144)
• FOXL2 gene mutations are a rare occurrence in isolated premature ovarian failure (POF) cases and may not be involved in the pathogenesis of POF. (PMID:18028747)
• FOXL2 polyAla expansions lead to protein mislocalization and aggregation in a length-dependent manner. (PMID:18158309)
• Missense mutations in the DNA-binding forkhead domain of FOXL2 lead to mislocalization, protein aggregation and altered transactivation. (PMID:18372316)
• analysis of the functional effects of novel mutations of the transcription factor FOXL2 in BPES patients (PMID:18484667)
• identified and characterized a FoxL2 response element (FLRE) and showed that it is highly specific and that it diverges from that of other Forkhead transcription factors (PMID:18635577)
• Novel mutations in the FOXL2 gene from Blepharophimosis syndrome patients have been found which confirm the existence of two previously described mutational hotspots. (PMID:18642388)
• Report the aberrant expression of FOXL2 in the human testis and its association with localized intratesticular sex reversal. (PMID:18721930)
• review of all currently described FOXL2 sequence variations and genomic rearrangements in blepharophimosis syndrome and premature ovarian failure (Review) (PMID:18726931)
• FOXL2 expression levels increase upon both oxidative stress and heat shock. (PMID:19010791)
• FoxL2 and Smad3 coordinately regulate follistatin gene transcription. (PMID:19106105)
• A novel role for FOXL2 in activin A-regulated Fshb transcription. (PMID:19324968)
• Mutations of the transcription factor FOXL2 gene in Chinese patients with BPES are reported. (PMID:19371227)
• Intranuclear aggregation and cytoplasmic mislocalization of mutant FOXL2 may be considered as loose predictors of ovarian dysfunction. (PMID:19515849)
• identified a single, recurrent somatic mutation (402C–>G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs (PMID:19516027)
• Deletion of the conserved non-coding sequences upstream of FOXL2 is associated with blepharophimosis syndrome. (PMID:19543368)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxl2a	ENSDARG00000042180
danio_rerio	foxl2b	ENSDARG00000068417
mus_musculus	Foxl2	ENSMUSG00000050397
rattus_norvegicus	Foxl2	ENSRNOG00000072374
drosophila_melanogaster	slp1	FBGN0003430
caenorhabditis_elegans		WBGENE00003976

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), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), 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 L2 — P58012 (reviewed: P58012)

All UniProt accessions (2): P58012, Q53ZD3

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans-differentiation of ovary to testis through transcriptional repression of the Sertoli cell-promoting gene SOX9. Has apoptotic activity in ovarian cells. Suppresses ESR1-mediated transcription of PTGS2/COX2 stimulated by tamoxifen. Is a regulator of CYP19 expression. Participates in SMAD3-dependent transcription of FST via the intronic SMAD-binding element. Is a transcriptional repressor of STAR. Activates SIRT1 transcription under cellular stress conditions. Activates transcription of OSR2.

Subunit / interactions. Interacts with ESR1. Interacts with SMAD3. Interacts with DDX20. Interacts with UBE2I/UBC9.

Subcellular location. Nucleus.

Tissue specificity. In addition to its expression in the developing eyelid, it is transcribed very early in somatic cells of the developing gonad (before sex determination) and its expression persists in the follicular cells of the adult ovary.

Post-translational modifications. Sumoylated with SUMO1; sumoylation is required for transcriptional repression activity.

Disease relevance. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) [MIM:110100] A disorder characterized by eyelid dysplasia, small palpebral fissures, drooping eyelids and a skin fold curving in the mediolateral direction, inferior to the inner canthus. In type I BPSE (BPES1) eyelid abnormalities are associated with female infertility. Affected females show an ovarian deficit due to primary amenorrhea or to premature ovarian failure (POF). In type II BPSE (BPES2) affected individuals show only the eyelid defects. The disease is caused by variants affecting the gene represented in this entry. There is a mutational hotspot in the region coding for the poly-Ala domain, since 30% of all mutations in the ORF lead to poly-Ala expansions, resulting mainly in BPES type II. Premature ovarian failure 3 (POF3) [MIM:608996] An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. The disease is caused by variants affecting the gene represented in this entry.

Induction. In granulosa-like cells, up-regulated at transcript and protein levels under oxidative stress and heat-shock conditions. Down-regulated by SIRT1.

RefSeq proteins (1): NP_075555* (*=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
IPR047515	FH_FOXL2	Domain
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (52 total): sequence variant 34, helix 5, compositionally biased region 3, strand 3, region of interest 2, chain 1, DNA-binding region 1, mutagenesis site 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7VOU	X-RAY DIFFRACTION	3.1
7VOV	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58012-F1	61.89	0.20

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 (2): 33, 25

Mutagenesis-validated functional residues (1):

Position	Phenotype
25	results in reduced sumoylation. loss of transcriptional repression activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3232118	SUMOylation of transcription factors
R-HSA-9690406	Transcriptional regulation of testis differentiation

MSigDB gene sets: 264 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_SINGLE_FERTILIZATION, GOBP_EPITHELIUM_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_GROWTH, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_SEX_DETERMINATION, GOBP_HORMONE_TRANSPORT, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_UP

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), ovarian follicle development (GO:0001541), oocyte growth (GO:0001555), extraocular skeletal muscle development (GO:0002074), apoptotic DNA fragmentation (GO:0006309), regulation of transcription by RNA polymerase II (GO:0006357), single fertilization (GO:0007338), anatomical structure morphogenesis (GO:0009653), female somatic sex determination (GO:0019101), cell differentiation (GO:0030154), positive regulation of luteinizing hormone secretion (GO:0033686), positive regulation of apoptotic process (GO:0043065), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of follicle-stimulating hormone secretion (GO:0046881), embryonic eye morphogenesis (GO:0048048), granulosa cell differentiation (GO:0060014), uterus development (GO:0060065), regulation of DNA-templated transcription (GO:0006355), female gonad development (GO:0008585), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (11): 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), DNA-binding transcription factor activity (GO:0003700), nuclear estrogen receptor binding (GO:0030331), ubiquitin conjugating enzyme binding (GO:0031624), cysteine-type endopeptidase regulator activity involved in apoptotic process (GO:0043028), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), Flemming body (GO:0090543)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
anatomical structure development	2
positive regulation of gonadotropin secretion	2
negative regulation of DNA-templated transcription	1
female gonad development	1
developmental process involved in reproduction	1
developmental cell growth	1
oocyte development	1
skeletal muscle tissue development	1
camera-type eye development	1
skeletal muscle organ development	1
DNA catabolic process	1
apoptotic nuclear changes	1
fertilization	1
developmental process	1
somatic sex determination	1
female sex determination	1
cellular developmental process	1
luteinizing hormone secretion	1
regulation of luteinizing hormone secretion	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
regulation of follicle-stimulating hormone secretion	1
follicle-stimulating hormone secretion	1
embryonic organ morphogenesis	1
eye morphogenesis	1
epithelial cell differentiation	1
animal organ development	1
reproductive structure development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
gonad development	1

Protein interactions and networks

STRING

1640 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXL2	NR5A1	Q13285	926
FOXL2	SMAD3	P84022	918
FOXL2	NOBOX	O60393	895
FOXL2	BMP15	O95972	891
FOXL2	FIGLA	Q6QHK4	890
FOXL2	SOX9	P48436	877
FOXL2	DDX20	Q9UHI6	853
FOXL2	DMRT1	Q9Y5R6	833
FOXL2	MRPS22	P82650	816
FOXL2	AMH	P03971	802
FOXL2	SRY	Q05066	802
FOXL2	OSR2	Q8N2R0	798
FOXL2	SMAD4	Q13485	793
FOXL2	WNT4	P56705	756
FOXL2	CYP19A1	P11511	756

IntAct

16 interactions, top by confidence:

A	B	Type	Score
FOXL2	Pias2	psi-mi:“MI:0915”(physical association)	0.370
FOXL2	Ube2i	psi-mi:“MI:0915”(physical association)	0.370
FOXL2	Sp100	psi-mi:“MI:0915”(physical association)	0.370
	FOXL2	psi-mi:“MI:0915”(physical association)	0.370
FOXL2	Ddx20	psi-mi:“MI:0915”(physical association)	0.370
FOXL2	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL2	RTCA	psi-mi:“MI:0914”(association)	0.350
SMAD4	FOXL2	psi-mi:“MI:2364”(proximity)	0.270
FOXL2	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	FOXL2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (71): FOXL2 (Biochemical Activity), DDX39A (Affinity Capture-MS), HNRNPUL2 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), YARS (Affinity Capture-MS), BTAF1 (Affinity Capture-MS), NSDHL (Affinity Capture-MS), PDS5A (Affinity Capture-MS), VARS (Affinity Capture-MS), ACSL4 (Affinity Capture-MS), ANP32C (Affinity Capture-MS), DCUN1D5 (Affinity Capture-MS), FUBP3 (Affinity Capture-MS), HK2 (Affinity Capture-MS), IARS (Affinity Capture-MS)

ESM2 similar proteins: A0A8I6AGW3, A2A9A2, A6NMB9, A8MYZ6, E9PZZ1, J3QK54, O02755, O02756, O35392, O35767, O60548, O70220, P05554, P17676, P21272, P28033, P35713, P42582, P49715, P49716, P52952, P53566, P58012, Q12952, Q13461, Q14526, Q60843, Q61345, Q63244, Q63250, Q6BEB4, Q6VFT5, Q6VFT6, Q6ZQN5, Q70KY4, Q8IU81, Q8MIP2, Q8NDY6, Q8R2I0, Q98937

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

12 interactions.

A	Effect	B	Mechanism
DDX20	up-regulates	FOXL2	binding
FOXL2	up-regulates	Apoptosis
FOXL2	“up-regulates quantity by expression”	SIRT1	“transcriptional regulation”
ROS	“up-regulates quantity by expression”	FOXL2
SIRT1	down-regulates	FOXL2	deacetylation
UBE2I	up-regulates	FOXL2	sumoylation
FOXL2	“down-regulates quantity by repression”	CYP11A1	“transcriptional regulation”
FOXL2	“down-regulates quantity by repression”	CCND2	“transcriptional regulation”
FOXL2	“down-regulates quantity by repression”	CYP19A1	“transcriptional regulation”
FOXL2	“down-regulates quantity by repression”	STAR	“transcriptional regulation”
FOXL2	up-regulates	Cell_death
LATS1	“up-regulates activity”	FOXL2	phosphorylation

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — OVT.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	131
Likely pathogenic	42
Uncertain significance	90
Likely benign	17
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1256027	NM_023067.4(FOXL2):c.871dup (p.His291fs)	Pathogenic
162043	NM_023067.4(FOXL2):c.142_173delinsGCGCT (p.Lys48_Ser58delinsAlaLeu)	Pathogenic
162044	NM_023067.4(FOXL2):c.965_983dup (p.Thr329fs)	Pathogenic
1699241	NM_023067.4(FOXL2):c.340A>T (p.Lys114Ter)	Pathogenic
1701464	NM_023067.4(FOXL2):c.673_*315inv (p.Ala225_Leu376delinsTrpAlaGlyAspAlaGlyAlaProGluArgAspGluProSerArgLysArgAlaGluArgGlnLeuGlnAlaArgGlyValGlnGlyHisArgGlyGlnGlyGlyGluHisArgArgThr)	Pathogenic
1705491	NM_023067.4(FOXL2):c.768dup (p.Pro257fs)	Pathogenic
1709921	NM_023067.4(FOXL2):c.871del (p.His291fs)	Pathogenic
180594	NM_023067.4(FOXL2):c.650C>T (p.Ser217Phe)	Pathogenic
180596	NM_023067.3(FOXL2):c.661GCN[15_24] (p.Ala221[(15_24)])	Pathogenic
180598	NM_023067.4(FOXL2):c.841_857dup (p.Pro287fs)	Pathogenic
180600	NM_023067.4(FOXL2):c.854del (p.Pro285fs)	Pathogenic
2006944	NM_023067.4(FOXL2):c.547del (p.Ala183fs)	Pathogenic
2018437	NM_023067.4(FOXL2):c.579del (p.Lys193fs)	Pathogenic
2049060	NM_023067.4(FOXL2):c.909del (p.Ala304fs)	Pathogenic
2097544	NM_023067.4(FOXL2):c.152del (p.Pro51fs)	Pathogenic
2151980	NM_023067.4(FOXL2):c.768del (p.Pro257fs)	Pathogenic
2203450	NM_023067.4(FOXL2):c.860del (p.Pro287fs)	Pathogenic
2203451	NM_023067.4(FOXL2):c.752_759del (p.Pro251fs)	Pathogenic
2662631	NM_023067.4(FOXL2):c.415G>T (p.Glu139Ter)	Pathogenic
2708580	NM_023067.4(FOXL2):c.369dup (p.Lys124fs)	Pathogenic
2715439	NM_023067.4(FOXL2):c.840_850dup (p.Pro284fs)	Pathogenic
2734577	NM_023067.4(FOXL2):c.223C>T (p.Leu75Phe)	Pathogenic
2734578	NM_023067.4(FOXL2):c.197C>A (p.Ala66Glu)	Pathogenic
2748834	NM_023067.4(FOXL2):c.881del (p.Pro294fs)	Pathogenic
2760710	NM_023067.4(FOXL2):c.283A>T (p.Lys95Ter)	Pathogenic
2766064	NM_023067.4(FOXL2):c.177C>G (p.Tyr59Ter)	Pathogenic
2780030	NM_023067.4(FOXL2):c.761C>A (p.Ser254Ter)	Pathogenic
2812820	NM_023067.4(FOXL2):c.249_250dup (p.Ile84fs)	Pathogenic
2812867	NM_023067.4(FOXL2):c.391_401del (p.Asp131fs)	Pathogenic
2815555	NM_023067.4(FOXL2):c.376_705del (p.Asn126_Gly235del)	Pathogenic

SpliceAI

62 predictions. Top by Δscore:

Variant	Effect	Δscore
3:138947073:G:GT	donor_gain	0.8100
3:138947098:T:TA	donor_gain	0.6500
3:138947072:C:CT	donor_gain	0.6400
3:138945642:A:T	acceptor_gain	0.5000
3:138945223:T:A	acceptor_gain	0.4500
3:138945549:C:A	donor_gain	0.4500
3:138945401:C:CC	acceptor_gain	0.4400
3:138947074:A:AA	donor_gain	0.4400
3:138945348:C:CT	acceptor_gain	0.4000
3:138947075:C:A	donor_gain	0.3600
3:138945397:TAAA:T	acceptor_gain	0.3300
3:138945399:AA:A	acceptor_gain	0.3300
3:138945195:CCGAC:C	acceptor_gain	0.3200
3:138945196:CGACC:C	acceptor_gain	0.3200
3:138945641:C:CT	acceptor_gain	0.3200
3:138947071:A:AC	donor_gain	0.3100
3:138945396:ATAAA:A	acceptor_gain	0.3000
3:138945455:G:T	donor_gain	0.3000
3:138945641:C:T	acceptor_gain	0.2900
3:138947063:C:A	donor_gain	0.2900
3:138945213:C:A	acceptor_gain	0.2800
3:138945432:A:AC	donor_gain	0.2800
3:138945433:G:C	donor_gain	0.2700
3:138945400:A:C	acceptor_gain	0.2600
3:138944543:T:C	acceptor_gain	0.2500
3:138945314:CCAG:C	acceptor_gain	0.2500
3:138945445:A:AC	donor_gain	0.2400
3:138945453:G:C	donor_gain	0.2400
3:138945459:C:T	donor_gain	0.2400
3:138945197:GAC:G	acceptor_loss	0.2300

AlphaMissense

2418 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:138946270:C:A	R151S	1.000
3:138946270:C:G	R151S	1.000
3:138946271:C:A	R151M	1.000
3:138946281:G:A	R148C	1.000
3:138946281:G:T	R148S	1.000
3:138946284:G:T	R147S	1.000
3:138946287:G:A	R146C	1.000
3:138946287:G:T	R146S	1.000
3:138946290:G:A	R145C	1.000
3:138946290:G:C	R145G	1.000
3:138946290:G:T	R145S	1.000
3:138946292:C:G	R144P	1.000
3:138946295:T:C	Y143C	1.000
3:138946296:A:C	Y143D	1.000
3:138946296:A:G	Y143H	1.000
3:138946296:A:T	Y143N	1.000
3:138946297:G:C	N142K	1.000
3:138946297:G:T	N142K	1.000
3:138946301:C:A	G141V	1.000
3:138946301:C:T	G141D	1.000
3:138946302:C:A	G141C	1.000
3:138946302:C:G	G141R	1.000
3:138946309:G:C	F138L	1.000
3:138946309:G:T	F138L	1.000
3:138946310:A:C	F138C	1.000
3:138946310:A:G	F138S	1.000
3:138946311:A:C	F138V	1.000
3:138946311:A:G	F138L	1.000
3:138946311:A:T	F138I	1.000
3:138946312:C:A	M137I	1.000

dbSNP variants (sampled 300 via entrez): RS1000078768 (3:138945417 G>A), RS1001047412 (3:138944633 C>CT), RS1001610604 (3:138943834 G>A), RS1001629364 (3:138948800 A>C,G), RS1003037092 (3:138947161 TC>T), RS1003189216 (3:138947612 A>G,T), RS1003632435 (3:138945701 G>A,T), RS1004645796 (3:138947713 T>C), RS1005787660 (3:138948960 G>A), RS1006121427 (3:138947089 G>T), RS1006153831 (3:138947263 A>G,T), RS1007559651 (3:138944049 C>T), RS1008665620 (3:138944962 G>A), RS1008748288 (3:138946996 T>A), RS1008770904 (3:138948302 T>C)

Disease associations

OMIM: gene MIM:605597 | disease phenotypes: MIM:110100, MIM:608996, MIM:126800

GenCC curated gene-disease

Disease	Classification	Inheritance
blepharophimosis, ptosis, and epicanthus inversus syndrome	Definitive	Autosomal dominant
premature ovarian failure 3	Limited	Unknown

Mondo (4): blepharophimosis, ptosis, and epicanthus inversus syndrome (MONDO:0007201), premature ovarian failure 3 (MONDO:0012169), Duane retraction syndrome (MONDO:0007473), blepharophimosis (MONDO:0001008)

Orphanet (3): Rare genetic premature ovarian failure (Orphanet:485382), Blepharophimosis-ptosis-epicanthus inversus syndrome (Orphanet:126), Duane retraction syndrome (Orphanet:233)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000141	Amenorrhea
HP:0000144	Decreased fertility
HP:0000147	Polycystic ovaries
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000322	Short philtrum
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000431	Wide nasal bridge
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000537	Epicanthus inversus
HP:0000539	Abnormality of refraction
HP:0000540	Hypermetropia
HP:0000568	Microphthalmia
HP:0000574	Thick eyebrow
HP:0000581	Blepharophimosis
HP:0000633	Decreased lacrimation
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000656	Ectropion
HP:0000769	Abnormality of the breast
HP:0000815	Hypergonadotropic hypogonadism
HP:0000837	Increased circulating gonadotropin level
HP:0000858	Irregular menstruation
HP:0000869	Secondary amenorrhea

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000773_3	Keloid	2.000000e-13
GCST002999_3	Lobe size	3.000000e-14
GCST003001_4	Ear morphology	2.000000e-11
GCST003476_7	Eyebrow thickness	4.000000e-10
GCST005192_117	Lobe attachment (rater-scored or self-reported)	3.000000e-49
GCST005193_18	Lobe attachment (rater scored)	5.000000e-13
GCST005193_5	Lobe attachment (rater scored)	2.000000e-18
GCST006661_139	Male-pattern baldness	3.000000e-19
GCST006706_1	Eyebrow thickness	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007666	lobe size
EFO:0007664	outer ear morphology trait
EFO:0007667	lobe attachment

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D016569	Blepharophimosis	C11.250.090; C11.338.190; C16.131.384.190
D004370	Duane Retraction Syndrome	C10.292.562.700.375.500; C11.270.235; C11.590.436.400.500; C16.320.290.235
C562419	Blepharophimosis, Ptosis, and Epicanthus Inversus (supp.)
C563816	Premature Ovarian Failure 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
mercuric bromide	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
TAK-243	increases sumoylation	1
dimethylselenide	increases expression, increases oxidation	1
arsenite	increases methylation	1
ferrous chloride	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
MK-8776	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects binding, decreases reaction, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Fluorouracil	increases expression	1
Ketoconazole	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polyribonucleotides	decreases expression, decreases reaction, increases expression	1
Tamoxifen	increases reaction, decreases reaction, increases activity, increases expression, affects binding	1
Testosterone	decreases expression	1
Tretinoin	increases expression	1
Mifepristone	decreases expression, decreases reaction, increases expression	1
Hydroxyl Radical	increases expression, increases oxidation	1
Magnetite Nanoparticles	increases methylation	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_0375	KGN	Cancer cell line	Female
CVCL_A2B5	SEES3-1V human FOXL2, clone1	Embryonic stem cell	Male
CVCL_A2B6	SEES3-1V human FOXL2, clone2	Embryonic stem cell	Male
CVCL_A2B7	SEES3-1V human FOXL2, clone3	Embryonic stem cell	Male
CVCL_C8VY	KGN-EGFP	Cancer cell line	Female
CVCL_E3DH	KGN-MXIV	Cancer cell line	Female
CVCL_E3DI	KGN-YAP	Cancer cell line	Female
CVCL_E3DJ	KGN-YAP(S127A)	Cancer cell line	Female
CVCL_F1R6	HyCyte KGN KO-hYTHDC2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06514612	PHASE3	RECRUITING	LIDRISE Study: A Phase 3 Study on the Efficacy and Safety of STN1013800 (Oxymetazoline HCl 0.1% Eye Drops, Single Dose) in the Treatment of Acquired Blepharoptosis.
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies