FOXD4

Summary

FOXD4 (forkhead box D4, HGNC:3805) is a protein-coding gene on chromosome 9p24.3, encoding Forkhead box protein D4 (Q12950). It is a common-essential gene (DepMap: required in 92.9% of cancer cell lines).

This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. Mutations in this gene are associated with a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorders, and suicidality.

Source: NCBI Gene 2298 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 139 total
• Cancer dependency (DepMap): dependent in 92.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_207305

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3805
Approved symbol	FOXD4
Name	forkhead box D4
Location	9p24.3
Locus type	gene with protein product
Status	Approved
Aliases	FREAC5, FOXD4a
Ensembl gene	ENSG00000170122
Ensembl biotype	protein_coding
OMIM	601092
Entrez	2298

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000382500

RefSeq mRNA: 1 — MANE Select: NM_207305 NM_207305

CCDS: CCDS34975

Canonical transcript exons

ENST00000382500 — 1 exons

Exon	Start	End
ENSE00001492340	116231	118417

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 66.68.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	66.68	gold quality
cerebellum	UBERON:0002037	62.89	gold quality
cerebellar cortex	UBERON:0002129	62.84	gold quality
cerebellar hemisphere	UBERON:0002245	62.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.49	gold quality
granulocyte	CL:0000094	55.96	gold quality
prefrontal cortex	UBERON:0000451	55.39	gold quality
putamen	UBERON:0001874	53.63	gold quality
frontal cortex	UBERON:0001870	53.54	gold quality
stromal cell of endometrium	CL:0002255	53.28	silver quality
brain	UBERON:0000955	53.24	gold quality
anterior cingulate cortex	UBERON:0009835	53.21	gold quality
cerebral cortex	UBERON:0000956	52.98	gold quality
caudate nucleus	UBERON:0001873	52.78	gold quality
hypothalamus	UBERON:0001898	52.58	gold quality
Ammon’s horn	UBERON:0001954	52.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	52.40	gold quality
ganglionic eminence	UBERON:0004023	52.26	gold quality
nucleus accumbens	UBERON:0001882	52.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	52.06	gold quality
amygdala	UBERON:0001876	51.88	gold quality
temporal lobe	UBERON:0001871	51.86	gold quality
primary visual cortex	UBERON:0002436	51.51	gold quality
right frontal lobe	UBERON:0002810	51.26	gold quality
right adrenal gland cortex	UBERON:0035827	50.60	gold quality
mucosa of transverse colon	UBERON:0004991	50.46	gold quality
lower esophagus	UBERON:0013473	49.80	gold quality
lower esophagus muscularis layer	UBERON:0035833	49.80	gold quality
apex of heart	UBERON:0002098	49.66	gold quality
adult mammalian kidney	UBERON:0000082	49.41	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-CURD-10	no	42.16
E-ANND-3	no	0.64

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
PC
SIRT1

miRNA regulators (miRDB)

31 targeting FOXD4, 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-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-12116	97.94	68.91	595
HSA-MIR-4642	97.52	67.60	916
HSA-MIR-645	97.28	66.30	486
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-454-5P	96.51	68.35	263
HSA-MIR-877-5P	94.62	66.30	710

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• The W148R mutation disrupts an extremely highly conserved tryptophan residue in the forkhead domain of FOXD4, possibly resulting in reduced DNA binding capacity and altered transcriptional activity. (PMID:17273782)
• FOXd4 encodes forkhead box D4 protein. (PMID:22876580)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Foxd4	ENSMUSG00000051490

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), 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 D4 — Q12950 (reviewed: Q12950)

Alternative names: Forkhead-related protein FKHL9, Forkhead-related transcription factor 5, Myeloid factor-alpha

All UniProt accessions (1): Q12950

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

RefSeq proteins (1): NP_997188* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (11 total): sequence variant 3, region of interest 3, compositionally biased region 3, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12950-F1	56.46	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 28 (showing top): KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, MORI_MATURE_B_LYMPHOCYTE_UP, GOMF_DNA_BINDING_BENDING, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_DN, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2_AND_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K4ME3_AND_H3K27ME3, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, MIR302C_5P, MIR3143, MIR507, MIR31_5P

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), anatomical structure morphogenesis (GO:0009653), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): 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 factor activity (GO:0003700), DNA binding, bending (GO:0008301), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA binding	2
transcription by RNA polymerase II	1
developmental process	1
anatomical structure development	1
cellular developmental process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

900 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXD4	ZNG1A	Q9BRT8	600
FOXD4	DMRT3	Q9NQL9	527
FOXD4	DMRT1	Q9Y5R6	449
FOXD4	KANK1	Q14678	447
FOXD4	DOCK8	Q8NF50	447
FOXD4	TIGD6	Q17RP2	395
FOXD4	DMRT2	Q9Y5R5	392
FOXD4	FOXR2	Q6PJQ5	387
FOXD4	ZIC2	O95409	325
FOXD4	FAM219A	Q8IW50	321
FOXD4	POU6F2	P78424	315
FOXD4	POU6F1	Q14863	309
FOXD4	NKX2-3	Q8TAU0	308
FOXD4	NKX3-2	P78367	308
FOXD4	LHX4	Q969G2	303

IntAct

24 interactions, top by confidence:

A	B	Type	Score
FOXD4	MDFI	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-6	FOXD4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-2	FOXD4	psi-mi:“MI:0915”(physical association)	0.560
FOXD4	AKAP8L	psi-mi:“MI:0915”(physical association)	0.560
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
FOXD4	PPP2R1B	psi-mi:“MI:0914”(association)	0.530
FOXD4	A2ML1	psi-mi:“MI:0914”(association)	0.350
FOXC1	FOXC1	psi-mi:“MI:0914”(association)	0.350
FOXD4	EIF5B	psi-mi:“MI:0914”(association)	0.350
FOXD4		psi-mi:“MI:0914”(association)	0.350
FOXD4	RECQL4	psi-mi:“MI:0914”(association)	0.350
CPA4	IGF1R	psi-mi:“MI:0914”(association)	0.350
CSNK1G3	FOXD4	psi-mi:“MI:0914”(association)	0.350
WBP4	COIL	psi-mi:“MI:0914”(association)	0.350
FOXD4	MDFI	psi-mi:“MI:0915”(physical association)	0.000
FOXD4	KRTAP10-6	psi-mi:“MI:0915”(physical association)	0.000
FOXD4	KRTAP12-2	psi-mi:“MI:0915”(physical association)	0.000
FOXD4	AKAP8L	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (87): FOXD4 (Affinity Capture-MS), CRYAB (Affinity Capture-MS), A2ML1 (Affinity Capture-MS), GSTP1 (Affinity Capture-MS), DMKN (Affinity Capture-MS), RALY (Affinity Capture-MS), TRIM29 (Affinity Capture-MS), FOXD4L1 (Affinity Capture-MS), RNASEH1 (Affinity Capture-MS), FOXD1 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), TACO1 (Affinity Capture-MS), EIF5B (Affinity Capture-MS), FOXD4L1 (Affinity Capture-MS), PDK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RRK4, A0A1W2PPE3, A0A1W2PR82, A0A2R8Y2Y2, A0A494C0N9, A0A494C0Y3, A0JNN8, A6NF83, A6NHQ4, A6QPM6, A8E4L3, A8MTW9, B2KGE5, C9JVW0, I3L1E1, O43541, O75474, O75638, P0C7X2, P70339, P89439, Q02080, Q05215, Q12950, Q3SYB3, Q5T230, Q5VV16, Q6NZ36, Q6NZY7, Q6P1X6, Q6VB84, Q6VUC0, Q6VUP9, Q6ZSJ8, Q7RTU5, Q7TNS8, Q80WY3, Q86SI9, Q86UU5, Q8K025

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	126
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

54 predictions. Top by Δscore:

Variant	Effect	Δscore
9:117497:C:CA	donor_gain	0.5900
9:117528:T:TA	donor_gain	0.5800
9:117150:T:A	donor_gain	0.5300
9:117204:T:TA	donor_gain	0.5100
9:117147:CT:C	donor_gain	0.4500
9:117176:T:TA	donor_gain	0.4400
9:117170:T:TA	donor_gain	0.4000
9:117146:A:AC	donor_gain	0.3900
9:117147:C:CC	donor_gain	0.3900
9:117271:G:A	donor_gain	0.3800
9:117177:C:A	donor_gain	0.3700
9:117208:C:CA	donor_gain	0.3600
9:117152:A:AC	donor_gain	0.3400
9:117223:CAAG:C	donor_gain	0.3400
9:117237:A:AC	donor_gain	0.3300
9:117127:C:A	donor_gain	0.3200
9:117220:G:T	donor_gain	0.3200
9:117282:T:A	donor_gain	0.3200
9:117190:CCAG:C	donor_gain	0.3100
9:117200:G:A	donor_gain	0.3100
9:117948:C:CT	donor_gain	0.2900
9:117949:C:CT	donor_gain	0.2900
9:116684:T:TC	acceptor_gain	0.2700
9:117031:C:CC	acceptor_gain	0.2700
9:117532:ACG:A	donor_gain	0.2700
9:117533:CGC:C	donor_gain	0.2700
9:116680:CATTT:C	acceptor_gain	0.2600
9:117207:T:TA	donor_gain	0.2600
9:117601:G:A	donor_gain	0.2600
9:118001:T:TA	donor_gain	0.2600

AlphaMissense

2793 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:117706:G:C	F138L	0.980
9:117706:G:T	F138L	0.980
9:117708:A:G	F138L	0.980
9:117634:G:C	F162L	0.977
9:117634:G:T	F162L	0.977
9:117636:A:G	F162L	0.977
9:117721:G:C	F133L	0.970
9:117721:G:T	F133L	0.970
9:117723:A:G	F133L	0.970
9:117556:G:C	F188L	0.961
9:117556:G:T	F188L	0.961
9:117558:A:G	F188L	0.961
9:117685:G:C	F145L	0.960
9:117685:G:T	F145L	0.960
9:117687:A:G	F145L	0.960
9:117676:C:A	W148C	0.949
9:117676:C:G	W148C	0.949
9:117731:A:G	I130T	0.946
9:117665:A:T	I152N	0.941
9:117541:A:C	F193L	0.940
9:117541:A:T	F193L	0.940
9:117543:A:G	F193L	0.940
9:117635:A:C	F162C	0.938
9:117644:T:A	N159I	0.938
9:117770:A:G	I117T	0.938
9:117665:A:G	I152T	0.934
9:117655:G:C	N155K	0.929
9:117655:G:T	N155K	0.929
9:117520:G:C	F200L	0.926
9:117520:G:T	F200L	0.926

dbSNP variants (sampled 300 via entrez): RS1001148465 (9:115951 C>T), RS1002196546 (9:116007 A>G), RS1002229110 (9:116606 G>A,C), RS1003199743 (9:117662 C>T), RS1003232473 (9:117826 A>G), RS1004564623 (9:118192 C>G), RS1004697185 (9:118016 T>A,C), RS1005567716 (9:119184 T>C), RS1005701923 (9:118861 C>T), RS1007254723 (9:119375 G>A,C), RS1007531273 (9:119992 A>C,T), RS1008909839 (9:117223 C>A,T), RS1009460266 (9:115991 A>G), RS1011470798 (9:118433 C>G,T), RS1012009045 (9:117985 C>A,G)

Disease associations

OMIM: gene MIM:601092 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Calcitriol	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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