FOXF2

Summary

FOXF2 (forkhead box F2, HGNC:3810) is a protein-coding gene on chromosome 6p25.3, encoding Forkhead box protein F2 (Q12947). Probable transcription activator for a number of lung-specific genes.

FOXF2 encodes forkhead box F2, one of many human homologues of the Drosophila melanogaster transcription factor forkhead. FOXF2 is expressed in lung and placenta, and has been shown to transcriptionally activate several lung-specific genes.

Source: NCBI Gene 2295 — RefSeq curated summary.

At a glance

• Gene–disease (curated): sensorineural hearing loss disorder (Moderate, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 88 total
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_001452

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3810
Approved symbol	FOXF2
Name	forkhead box F2
Location	6p25.3
Locus type	gene with protein product
Status	Approved
Aliases	FREAC2
Ensembl gene	ENSG00000137273
Ensembl biotype	protein_coding
OMIM	603250
Entrez	2295

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000645481

RefSeq mRNA: 1 — MANE Select: NM_001452 NM_001452

CCDS: CCDS4472

Canonical transcript exons

ENST00000645481 — 2 exons

Exon	Start	End
ENSE00000847764	1394696	1395603
ENSE00003820499	1389576	1391118

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 96.49.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8066 / max 221.4290, expressed in 835 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65422	4.4890	792
65425	0.5930	307
65423	0.5690	247
65424	0.1556	78

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	96.49	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.00	gold quality
lower esophagus	UBERON:0013473	94.93	gold quality
urethra	UBERON:0000057	94.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.16	gold quality
mucosa of stomach	UBERON:0001199	91.33	gold quality
lower lobe of lung	UBERON:0008949	89.26	gold quality
pylorus	UBERON:0001166	87.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.07	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.07	gold quality
right lung	UBERON:0002167	86.70	gold quality
sigmoid colon	UBERON:0001159	84.88	gold quality
esophagus	UBERON:0001043	83.83	gold quality
ileal mucosa	UBERON:0000331	83.32	gold quality
transverse colon	UBERON:0001157	82.87	gold quality
lung	UBERON:0002048	82.61	gold quality
colon	UBERON:0001155	82.45	gold quality
upper lobe of lung	UBERON:0008948	82.44	gold quality
large intestine	UBERON:0000059	82.11	gold quality
upper lobe of left lung	UBERON:0008952	82.05	gold quality
intestine	UBERON:0000160	81.31	gold quality
fundus of stomach	UBERON:0001160	81.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.65	gold quality
cardia of stomach	UBERON:0001162	80.35	gold quality
stomach	UBERON:0000945	80.20	gold quality
body of stomach	UBERON:0001161	80.10	gold quality
rectum	UBERON:0001052	79.90	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.59	gold quality
small intestine	UBERON:0002108	79.06	gold quality
lower esophagus mucosa	UBERON:0035834	78.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.44

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
BAMBI	Activation
CDH1
CXCL12	Activation
GH2
IRF2BPL	Activation
ITGB1	Repression
MT1E	Repression
MT1F	Repression
PDGFA	Repression
PSG7	Repression
SFTPB	Activation
TLN1
WASF2	Activation

JASPAR motifs

Motif	Name	Family
MA0030.1	FOXF2	FOX
MA0030.2	FOXF2	FOX

JASPAR matrix evidence (PMIDs): PMID:7957066

miRNA regulators (miRDB)

69 targeting FOXF2, 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-8485	100.00	77.57	4731
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
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-605-3P	99.88	69.22	1833
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870

Literature-anchored findings (GeneRIF, showing 40)

• 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development (PMID:19276632)
• The distinct expression pattern of FOXF2 in the prostate, its effect on expression of signaling, and its opposing role in the TGFbeta3 pathway, suggests a role for FOXF2 in prostate homeostasis and stroma-epithelial interactions (PMID:19562724)
• MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer. (PMID:23383207)
• decreased FOXF2 expression indicates the early-onset metastasis and poor prognosis for patients with histological grade II and triple-negative breast cancer. (PMID:23620774)
• MiR-182-induced downregulation of FoxF2. (PMID:25738520)
• The miR-200 family and the miR-18396182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers. (PMID:25798833)
• Loss of FOXF2 Expression is associated with Hepatocellular Carcinoma. (PMID:25824262)
• Subtype-specific expression and function of FOXF2 in breast cancer cells are regulated through the combined effects of DNA methylation and SP1 transcriptional regulation. (PMID:26070560)
• Foxf2 inactivation in adults resulted in blood-brain barrier breakdown, endothelial thickening, and increased trans-endothelial vesicular transport (PMID:26120030)
• results provided statistical evidence of linkage and association between FOXF2 and nonsyndromic cleft lip with or without cleft palate. (PMID:26278207)
• Common variants near FOXF2 that are associated with increased stroke susceptibility. (PMID:27068588)
• FOXF2 has a dual role in breast tumorigenesis and functions as either a tumor suppressor or an oncogene depending on the breast tumor subtype. (PMID:27377963)
• Cox proportional hazards regression model was used to evaluate the predictive value of FOXF2 mRNA level in non-small cell lung cancer patients (PMID:27487137)
• miR-182 may promote cell proliferation and migration in triple-negative breast cancer possibly via down-regulation of FOXF2. (PMID:28043147)
• No correlation was found between FOXF2 promoter methylation and other clinic pathological parameters (age, gender, differentiation, lymph node metastasis, stage, cutting edge, vascular invasion, smoking behavior, and drinking history) in esophageal squamous cell carcinoma. (PMID:28222662)
• direct targeting of Foxf2 by Shh signaling drives cranial neural crest cell mesenchyme proliferation during upper lip morphogenesis, and disruption of this sequence results in cleft lip. (PMID:28506991)
• MAZ/FOXF2 axis can promote the proliferation of basal like breast cancer cells and suppress disease progression. (PMID:28577976)
• FOXF2 deficiency induced mesenchymal-epithelial transition (MET) in Huh7 cell which might facilitate the colonization of circulating tumor cells and the formation of metastasis. (PMID:28582850)
• FOXF2 rs1711972 AA genotype is associated with poor response to therapy in Non-small Cell Lung Cancer. (PMID:28766235)
• miR130a can regulate FOXF2 and function as an oncogene in colorectal cancer. (PMID:28849155)
• FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of beta-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. (PMID:29374064)
• Data revealed that FOXF2 deficiency promotes the lymphatic metastasis of basal-like breast cancer (BLBC by conferring a lymphangiogenic mimetic feature upon cancer cells through direct activation of the VEGF-C/VEGFR3 signaling pathway. (PMID:29409810)
• Nude mouse xenograft assay was performed to test Hela cells proliferation ability in vivo FOXF2 and b-catenin positive cell numbers were detected by immunohistochemistry.Low FOXF2 expression predicted poor outcomes of cervical cancer patients. (PMID:30249755)
• lncRNA ADAMTS9-AS2 decreased OC progression by regulating miR-182-5p/FOXF2 axis (PMID:30268751)
• Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients (PMID:30565344)
• mutual transcriptional repression between FOXF2 and FOXQ1, and the reciprocal negative feedback loop controlled EMT, aggressiveness, and chemoresistance in basal-like breast cancer cells. (PMID:30807702)
• We have identified a putative dominantly acting missense mutation in the activation domain of FOXF2, which fully segregates in a multigeneration family that includes 8 affected individuals. All present with absent uvula, short anterior border of the soft palate, and abnormal pillars of the fauces. (PMID:30917284)
• Study shows that forkhead box F2 (FOXF2) functions as a master transcription factor for reprogramming cancer cells into an osteomimetic phenotype by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. (PMID:31222004)
• FOXF2 aggravates the progression of non-small cell lung cancer through targeting lncRNA H19 to downregulate PTEN. (PMID:31858547)
• Cell-to-Cell Variation in Gene Expression for Cultured Human Cells Is Controlled in Trans by Diverse Genes: Implications for the Pathobiology of Aging. (PMID:31957802)
• Foxf2 and Smad6 co-regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion. (PMID:32022446)
• FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-beta and miR-182-5p. (PMID:32424142)
• si-SNHG5-FOXF2 inhibits TGF-beta1-induced fibrosis in human primary endometrial stromal cells by the Wnt/beta-catenin signalling pathway. (PMID:33176855)
• A Methylome and Transcriptome Analysis of Normal Human Scar Cells Reveals a Role for FOXF2 in Scar Maintenance. (PMID:34687743)
• miRNA-182-5p promotes human bladder cancer proliferation and migration through the FOXF2/SHH axis. (PMID:35068163)
• FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/beta-catenin pathway. (PMID:35660418)
• FOXF2 Regulates PRUNE2 Transcription in the Pathogenesis of Colorectal Cancer. (PMID:35929169)
• Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer. (PMID:35994645)
• Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity. (PMID:36369237)
• Transcription factor FOXF2 promotes the development and progression of pancreatic cancer by targeting MSI2. (PMID:38847273)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxp1a	ENSDARG00000004843
danio_rerio	foxp1b	ENSDARG00000014181
mus_musculus	Foxf2	ENSMUSG00000038402
rattus_norvegicus	Foxf2	ENSRNOG00000063796

Paralogs (4): FOXP2 (ENSG00000128573), FOXP4 (ENSG00000137166), FOXI1 (ENSG00000168269), FOXG1 (ENSG00000176165)

Protein

Protein identifiers

Forkhead box protein F2 — Q12947 (reviewed: Q12947)

Alternative names: Forkhead-related activator 2, Forkhead-related protein FKHL6, Forkhead-related transcription factor 2

All UniProt accessions (1): Q12947

UniProt curated annotations — full annotation on UniProt →

Function. Probable transcription activator for a number of lung-specific genes. Mediates up-regulation of the E3 ligase IRF2BPL and drives ubiquitination and degradation of CTNNB1.

Subunit / interactions. Interacts with the transcription factors TBP and TFIIB.

Subcellular location. Nucleus.

Tissue specificity. Lung and placenta. Predominantly expressed in gastrointestinal tract including stomach.

Domain organisation. Two activation domains, AD1 and AD2, C-terminal of (and distinct from) the forkhead domains are necessary for transcriptional activation.

RefSeq proteins (1): NP_001443* (*=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 (10 total): compositionally biased region 5, region of interest 3, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12947-F1	58.04	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 215 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, TGCACTT_MIR519C_MIR519B_MIR519A, MODULE_545, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CHX10_01, chr6p25, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, CDP_01, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GERY_CEBP_TARGETS

GO Biological Process (16): epithelial to mesenchymal transition (GO:0001837), regulation of transcription by RNA polymerase II (GO:0006357), animal organ morphogenesis (GO:0009887), extracellular matrix organization (GO:0030198), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), establishment of planar polarity of embryonic epithelium (GO:0042249), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic digestive tract development (GO:0048566), embryonic camera-type eye morphogenesis (GO:0048596), genitalia development (GO:0048806), roof of mouth development (GO:0060021), regulation of protein polyubiquitination (GO:1902914), regulation of DNA-templated transcription (GO:0006355), system development (GO:0048731)

GO Molecular Function (9): 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), TFIIB-class transcription factor binding (GO:0001093), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), general transcription initiation factor binding (GO:0140296)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nuclear body (GO:0016604)

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
transcription by RNA polymerase II	2
animal organ development	2
regulation of transcription by RNA polymerase II	2
anatomical structure development	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
mesenchymal cell differentiation	1
anatomical structure morphogenesis	1
extracellular structure organization	1
external encapsulating structure organization	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
establishment of planar polarity	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
digestive tract development	1
embryonic organ development	1
embryonic camera-type eye development	1
embryonic eye morphogenesis	1
camera-type eye morphogenesis	1
sex differentiation	1
reproductive structure development	1
protein polyubiquitination	1
regulation of protein ubiquitination	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
multicellular organism development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
RNA polymerase II general transcription initiation factor binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1

Protein interactions and networks

STRING

1434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXF2	GMDS	O60547	779
FOXF2	CYP1B1	Q16678	690
FOXF2	SFTPB	P07988	670
FOXF2	TPPP	O94811	647
FOXF2	PITX2	Q99697	638
FOXF2	BMP4	P12644	591
FOXF2	FOXQ1	Q9C009	563
FOXF2	GATA6	P78327	560
FOXF2	CTNNB1	P35222	550
FOXF2	SCGB1A1	P11684	518
FOXF2	GLI3	P10071	510
FOXF2	GLI1	P08151	497
FOXF2	GLI2	P10070	497
FOXF2	SOX5	P35711	441
FOXF2	NQO1	P15559	429

IntAct

28 interactions, top by confidence:

A	B	Type	Score
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
CCNJL	PIK3C2A	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
THBS2	AP1G2	psi-mi:“MI:0914”(association)	0.530
CRYBA4	RBP4	psi-mi:“MI:0914”(association)	0.530
ABL1	FOXF2	psi-mi:“MI:0915”(physical association)	0.400
FOXF2	FYN	psi-mi:“MI:0915”(physical association)	0.400
FOXJ2	TCERG1	psi-mi:“MI:0914”(association)	0.350
P4HA2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
PRG2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
PROZ	ARVCF	psi-mi:“MI:0914”(association)	0.350
CRYBA4	APAF1	psi-mi:“MI:0914”(association)	0.350
ADAM30	PLXNA2	psi-mi:“MI:0914”(association)	0.350
MLST8	LYPLA2	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
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
PROZ	MAP2K7	psi-mi:“MI:0914”(association)	0.350
ADAM30	MBTPS2	psi-mi:“MI:0914”(association)	0.350
FOXF2	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), FOXF2 (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

4 interactions.

A	Effect	B	Mechanism
FOXF2	“up-regulates quantity by expression”	IRF2BPL	“transcriptional regulation”
hsa-miR-182-5p	“down-regulates quantity by destabilization”	FOXF2	“post transcriptional regulation”
GTF2B	“up-regulates activity”	FOXF2	binding
FOXF2	“up-regulates activity”	TBP	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	11
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

300 predictions. Top by Δscore:

Variant	Effect	Δscore
6:1394694:AGT:A	acceptor_gain	1.0000
6:1394695:GTG:G	acceptor_gain	1.0000
6:1391114:CTCAG:C	donor_loss	0.9900
6:1391115:TCAGG:T	donor_loss	0.9900
6:1391116:CAG:C	donor_loss	0.9900
6:1391117:AGG:A	donor_loss	0.9900
6:1391118:GG:G	donor_loss	0.9900
6:1391119:G:C	donor_loss	0.9900
6:1391120:T:A	donor_loss	0.9900
6:1394690:TTTCA:T	acceptor_loss	0.9900
6:1394691:TTCA:T	acceptor_loss	0.9900
6:1394692:TCA:T	acceptor_loss	0.9900
6:1394693:CAGTG:C	acceptor_loss	0.9900
6:1394694:A:AG	acceptor_gain	0.9900
6:1394694:AGTG:A	acceptor_gain	0.9900
6:1394694:AGTGG:A	acceptor_gain	0.9900
6:1394695:G:GG	acceptor_gain	0.9900
6:1394695:GT:G	acceptor_gain	0.9900
6:1394695:GTGG:G	acceptor_gain	0.9900
6:1394695:GTGGG:G	acceptor_gain	0.9900
6:1394063:G:GT	donor_gain	0.8900
6:1392656:A:T	donor_gain	0.8800
6:1393894:TC:T	donor_gain	0.8700
6:1394697:G:A	acceptor_gain	0.8700
6:1394185:G:GT	donor_gain	0.8600
6:1392655:G:GT	donor_gain	0.8000
6:1394157:T:TA	donor_gain	0.7900
6:1392635:G:GT	donor_gain	0.7700
6:1394110:G:GT	donor_gain	0.7500
6:1394107:C:T	donor_gain	0.7400

AlphaMissense

2882 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:1390245:A:C	K100Q	1.000
6:1390245:A:G	K100E	1.000
6:1390246:A:T	K100M	1.000
6:1390247:G:C	K100N	1.000
6:1390247:G:T	K100N	1.000
6:1390248:C:A	P101T	1.000
6:1390248:C:T	P101S	1.000
6:1390249:C:A	P101Q	1.000
6:1390249:C:G	P101R	1.000
6:1390254:T:G	Y103D	1.000
6:1390258:C:G	S104W	1.000
6:1390258:C:T	S104L	1.000
6:1390260:T:C	Y105H	1.000
6:1390261:A:G	Y105C	1.000
6:1390263:A:T	I106F	1.000
6:1390264:T:A	I106N	1.000
6:1390264:T:C	I106T	1.000
6:1390264:T:G	I106S	1.000
6:1390267:C:A	A107E	1.000
6:1390269:C:T	L108F	1.000
6:1390270:T:A	L108H	1.000
6:1390270:T:C	L108P	1.000
6:1390270:T:G	L108R	1.000
6:1390272:A:T	I109F	1.000
6:1390273:T:A	I109N	1.000
6:1390273:T:G	I109S	1.000
6:1390276:T:A	V110D	1.000
6:1390279:T:C	M111T	1.000
6:1390279:T:G	M111R	1.000
6:1390280:G:A	M111I	1.000

dbSNP variants (sampled 300 via entrez): RS1000245913 (6:1389375 C>A), RS1000527471 (6:1390903 C>T), RS1000536999 (6:1390736 G>A,T), RS1000873883 (6:1395327 C>T), RS1001189085 (6:1393395 CCTG>C), RS1001203646 (6:1393158 C>A,G), RS1002198835 (6:1392484 G>A), RS1002259450 (6:1392776 T>C), RS1003123374 (6:1393519 G>A), RS1003260983 (6:1393759 C>T), RS1003355064 (6:1391862 T>G), RS1003374409 (6:1389668 C>A,G,T), RS1003795316 (6:1389420 A>G), RS1004280522 (6:1388356 C>G,T), RS1004486415 (6:1388735 C>T)

Disease associations

OMIM: gene MIM:603250 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
sensorineural hearing loss disorder	Moderate	Autosomal recessive

Mondo (1): sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST002397_1	Bladder cancer (smoking interaction)	3.000000e-06
GCST003491_1	Stroke	1.000000e-08
GCST003518_8	Daytime sleep phenotypes	1.000000e-06
GCST003527_2	Anti-thyroid drug induced agranulocytosis	7.000000e-11
GCST003810_4	Non-response to citalopram or escitalopram and depression	9.000000e-07
GCST003944_37	Hepcidin/ferritin ratio	8.000000e-06
GCST005170_33	Intraocular pressure	4.000000e-17
GCST005580_197	Intraocular pressure	2.000000e-27
GCST005580_218	Intraocular pressure	4.000000e-21
GCST006956_4	Erectile dysfunction	3.000000e-06
GCST009391_1587	Metabolite levels	9.000000e-06
GCST011947_32	White matter hyperintensity volume	3.000000e-06
GCST011949_39	White matter hyperintensity volume (adjusted for hypertension)	8.000000e-06
GCST011950_19	White matter hyperintensity volume (adjusted for hypertension)	2.000000e-06
GCST90011766_2	Glaucoma (primary open-angle)	9.000000e-20
GCST90011770_2	Glaucoma (primary open-angle)	1.000000e-40

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007838	response to anti-thyroid drug
EFO:0007901	hepcidin:ferritin ratio
EFO:0004695	intraocular pressure measurement
EFO:0010349	cholesteryl ester 20:5 measurement
EFO:0005665	white matter hyperintensity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs199564443	Toxicity	3	Antithyroid Preparations	Agranulocytosis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs199564443	FOXF2	3	0.00	1	Antithyroid Preparations

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects expression, affects cotreatment	3
Aflatoxin B1	decreases methylation, increases expression, increases methylation	3
Benzo(a)pyrene	increases expression, increases methylation, affects methylation	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
arsenite	increases methylation	1
tobacco tar	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
1,2,5,6-dibenzanthracene	increases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
cupric oxide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases 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
Temozolomide	affects response to substance	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cadmium	increases expression	1
Calcitriol	decreases expression	1
Carmustine	affects response to substance	1
Curcumin	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Endosulfan	increases expression	1
Etoposide	affects response to substance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study
NCT02698787	Not specified	COMPLETED	Fundamental Asynchronous Stimulus Timing Sound Coding Study
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry