FOXD4L1

Summary

FOXD4L1 (forkhead box D4 like 1, HGNC:18521) is a protein-coding gene on chromosome 2q14.1, encoding Forkhead box protein D4-like 1 (Q9NU39). It is a selective cancer dependency (DepMap: 80.0% of cell lines).

This gene is a member of the forkhead/winged-helix (FOX) family of transcription factors with highly conserved FOX DNA-binding domains. Members of the FOX family of transcription factors are regulators of embryogenesis and may play a role in human cancer. This gene lies in a region of chromosome 2 that surrounds the site where two ancestral chromosomes fused to form human chromosome 2. This region is duplicated elsewhere in the human genome, primarily in subtelomeric and pericentromeric locations, thus mutiple copies of this gene have been found.

Source: NCBI Gene 200350 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 83 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 80.0% of screened cell lines
• MANE Select transcript: NM_012184

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18521
Approved symbol	FOXD4L1
Name	forkhead box D4 like 1
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	FOXD5
Ensembl gene	ENSG00000184492
Ensembl biotype	protein_coding
OMIM	611084
Entrez	200350

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000306507

RefSeq mRNA: 1 — MANE Select: NM_012184 NM_012184

CCDS: CCDS2117

Canonical transcript exons

ENST00000306507 — 1 exons

Exon	Start	End
ENSE00003978204	113498665	113501150

Expression profiles

Bgee: expression breadth broad, 61 present calls, max score 61.48.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	61.48	gold quality
cortical plate	UBERON:0005343	55.05	gold quality
cerebellum	UBERON:0002037	54.85	gold quality
cerebellar cortex	UBERON:0002129	54.72	gold quality
cerebellar hemisphere	UBERON:0002245	54.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	52.67	gold quality
bone marrow cell	CL:0002092	52.14	gold quality
stromal cell of endometrium	CL:0002255	51.71	silver quality
bone marrow	UBERON:0002371	50.83	gold quality
primary visual cortex	UBERON:0002436	46.49	silver quality
putamen	UBERON:0001874	46.08	gold quality
nucleus accumbens	UBERON:0001882	45.97	gold quality
superior frontal gyrus	UBERON:0002661	45.76	silver quality
caudate nucleus	UBERON:0001873	45.50	gold quality
prefrontal cortex	UBERON:0000451	45.02	silver quality
embryo	UBERON:0000922	44.77	silver quality
ganglionic eminence	UBERON:0004023	44.77	silver quality
brain	UBERON:0000955	44.64	gold quality
right adrenal gland cortex	UBERON:0035827	44.36	silver quality
vermiform appendix	UBERON:0001154	44.35	gold quality
right uterine tube	UBERON:0001302	44.03	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	43.74	gold quality
cerebral cortex	UBERON:0000956	43.63	gold quality
frontal cortex	UBERON:0001870	43.55	silver quality
Ammon’s horn	UBERON:0001954	43.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	43.33	silver quality
right adrenal gland	UBERON:0001233	43.25	silver quality
anterior cingulate cortex	UBERON:0009835	43.24	gold quality
lower esophagus mucosa	UBERON:0035834	43.15	silver quality
hindlimb stylopod muscle	UBERON:0004252	42.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting FOXD4L1, 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-5195-3P	99.92	70.92	1877
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-410-3P	99.27	69.98	2457
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-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 80.0% of screened cell lines.

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), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), 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-like 1 — Q9NU39 (reviewed: Q9NU39)

All UniProt accessions (1): Q9NU39

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

RefSeq proteins (1): NP_036316* (*=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
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (9 total): region of interest 3, compositionally biased region 3, chain 1, DNA-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NU39-F1	59.24	0.17

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 36 (showing top): BENPORATH_ES_WITH_H3K27ME3, chr2q14, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, KUMAR_PATHOGEN_LOAD_BY_MACROPHAGES, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, MIR302C_5P, MIR3143, MIR31_5P, GSE10273_LOW_IL7_VS_HIGH_IL7_AND_IRF4_IN_IRF4_8_NULL_PRE_BCELL_DN, GSE1448_CTRL_VS_ANTI_VALPHA2_DP_THYMOCYTE_DN, GSE17721_PAM3CSK4_VS_CPG_24H_BMDC_UP, GSE17721_LPS_VS_PAM3CSK4_24H_BMDC_DN, GSE17721_12H_VS_24H_GARDIQUIMOD_BMDC_UP, GSE2197_IMMUNOSUPPRESSIVE_DNA_VS_UNTREATEDIN_DC_DN, GOMF_DNA_BINDING_TRANSCRIPTION_FACTOR_ACTIVITY

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 (6): 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 (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

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
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
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXD4L1	SOX11	P35716	441
FOXD4L1	ZIC2	O95409	404
FOXD4L1	TPBGL	P0DKB5	350
FOXD4L1	TIGD6	Q17RP2	322
FOXD4L1	ETV3L	Q6ZN32	317
FOXD4L1	ZIC1	Q15915	312
FOXD4L1	SOX3	P35714	306
FOXD4L1	IRX1	P78414	302
FOXD4L1	POU5F2	Q8N7G0	298
FOXD4L1	NBPF14	Q5TI25	295
FOXD4L1	CHRD	Q9H2X0	292
FOXD4L1	NKX1-1	Q15270	275
FOXD4L1	HOXC13	P31276	274
FOXD4L1	TLE5	Q08117	273
FOXD4L1	B3GNT4	Q9C0J1	272

IntAct

80 interactions, top by confidence:

A	B	Type	Score
RBPMS2	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.600
FOXD4L1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
BOLL	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
DAZAP2	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
PRDM6	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
GPRASP2	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
MDFI	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-2	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
EXOSC8	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
KRT34	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
PSME3	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPK	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
BAG3	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-2	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
FOXD4L1	MAPRE3	psi-mi:“MI:0915”(physical association)	0.560
FOXD4L1	WWOX	psi-mi:“MI:0915”(physical association)	0.560
FOXD4L1	ABI2	psi-mi:“MI:0915”(physical association)	0.560
HGS	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
CARD9	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
HMG20A	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	FOXD4L1	psi-mi:“MI:0915”(physical association)	0.560
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
FOXD4	EIF5B	psi-mi:“MI:0914”(association)	0.350
FOXD4		psi-mi:“MI:0914”(association)	0.350

BioGRID (30): FOXD4L1 (Affinity Capture-MS), FOXD4L1 (Affinity Capture-MS), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid), FOXD4L1 (Two-hybrid)

ESM2 similar proteins: A0A1W2PRP0, A6NCS4, A7Y7W2, O14512, O43638, O57601, O70220, O96004, P07812, P09023, P10085, P10284, P17483, P22091, P24899, P50548, P52954, P52955, P55318, P57100, P63156, P63157, P70447, P79772, P97832, Q02346, Q05917, Q0VCE2, Q12952, Q1XID0, Q28555, Q3I5G5, Q3Y598, Q60688, Q61660, Q63244, Q63250, Q64279, Q64305, Q64731

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

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	78
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
442204	GRCh37/hg19 2q13-14.3(chr2:114056441-123673800)x1	Pathogenic

SpliceAI

61 predictions. Top by Δscore:

Variant	Effect	Δscore
2:113498780:T:G	donor_gain	0.9400
2:113499170:A:AG	acceptor_gain	0.8700
2:113499171:A:G	acceptor_gain	0.8400
2:113498779:GT:G	donor_gain	0.7800
2:113498780:TT:T	donor_gain	0.7800
2:113498780:T:TG	donor_gain	0.7600
2:113499169:CAACA:C	acceptor_gain	0.6100
2:113499153:G:A	acceptor_gain	0.6000
2:113498770:T:TA	donor_gain	0.5900
2:113499168:GCAAC:G	acceptor_gain	0.5300
2:113499167:TGCAA:T	acceptor_gain	0.5200
2:113499170:AACA:A	acceptor_gain	0.5000
2:113499181:CAGG:C	acceptor_gain	0.4700
2:113499173:A:T	acceptor_gain	0.4500
2:113499175:TCATC:T	acceptor_gain	0.4300
2:113499176:CATCC:C	acceptor_gain	0.4300
2:113499177:ATCC:A	acceptor_gain	0.4300
2:113499179:C:T	acceptor_gain	0.4200
2:113499180:CCAGG:C	acceptor_gain	0.4200
2:113499182:AGGC:A	acceptor_gain	0.4100
2:113499160:TGC:T	acceptor_gain	0.4000
2:113499173:A:AG	acceptor_gain	0.3700
2:113499180:C:CA	acceptor_gain	0.3700
2:113499161:G:T	acceptor_gain	0.3600
2:113499162:C:T	acceptor_gain	0.3600
2:113498990:G:GT	donor_gain	0.3400
2:113499184:GCT:G	acceptor_gain	0.3300
2:113499181:C:CT	acceptor_gain	0.3200
2:113499171:ACA:A	acceptor_gain	0.3100
2:113499166:TTGCA:T	acceptor_gain	0.3000

AlphaMissense

2595 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:113499662:T:C	F136L	0.996
2:113499664:C:A	F136L	0.996
2:113499664:C:G	F136L	0.996
2:113499677:T:C	F141L	0.996
2:113499679:C:A	F141L	0.996
2:113499679:C:G	F141L	0.996
2:113499749:T:C	F165L	0.996
2:113499751:C:A	F165L	0.996
2:113499751:C:G	F165L	0.996
2:113499827:T:C	F191L	0.996
2:113499829:C:A	F191L	0.996
2:113499829:C:G	F191L	0.996
2:113499720:T:A	I155N	0.995
2:113499750:T:G	F165C	0.995
2:113499709:G:C	W151C	0.994
2:113499709:G:T	W151C	0.994
2:113499725:C:G	H157D	0.994
2:113499654:T:C	I133T	0.993
2:113499707:T:A	W151R	0.992
2:113499707:T:C	W151R	0.992
2:113499720:T:C	I155T	0.992
2:113499741:A:T	N162I	0.992
2:113499750:T:C	F165S	0.992
2:113499828:T:G	F191C	0.992
2:113499666:T:A	I137N	0.990
2:113499720:T:G	I155S	0.990
2:113499732:T:A	L159H	0.990
2:113499799:G:C	W181C	0.990
2:113499799:G:T	W181C	0.990
2:113499654:T:G	I133S	0.989

dbSNP variants (sampled 300 via entrez): RS1000653589 (2:113497062 C>T), RS1001583647 (2:113498229 T>G), RS1006589313 (2:113498943 G>A,C,T), RS1010292506 (2:113496999 A>G), RS1013078439 (2:113501390 G>A,T), RS1013477377 (2:113498294 G>A,T), RS1013832123 (2:113498845 G>A), RS1018019057 (2:113498979 T>C), RS1020461078 (2:113499023 G>A), RS1020850011 (2:113499381 A>G), RS1022115552 (2:113497006 T>C), RS1024622029 (2:113497165 CT>C), RS1024696949 (2:113500130 C>T), RS1025291093 (2:113498303 A>G), RS1026327292 (2:113500644 A>C,G)

Disease associations

OMIM: gene MIM:611084 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008841_1	Depressive symptom (sleep problems) (binary trait)	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Hydralazine	increases expression, affects cotreatment	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1Y3	SEES3-1V human FOXD4L1, clone1	Embryonic stem cell	Male
CVCL_A1Y4	SEES3-1V human FOXD4L1, clone2	Embryonic stem cell	Male

Clinical trials (associated diseases)

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