FBXO46

Summary

FBXO46 (F-box protein 46, HGNC:25069) is a protein-coding gene on chromosome 19q13.32, encoding F-box only protein 46 (Q6PJ61). Substrate-recognition component of the SCF(FBXO46) protein ligase complex, which mediates the ubiquitination and degradation of target proteins.

Members of the F-box protein family, such as FBXO46, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).

Source: NCBI Gene 23403 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_001080469

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25069
Approved symbol	FBXO46
Name	F-box protein 46
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	20D7-FC4, Fbx46
Ensembl gene	ENSG00000177051
Ensembl biotype	protein_coding
OMIM	609117
Entrez	23403

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000317683, ENST00000586899, ENST00000591686, ENST00000925224, ENST00000925225, ENST00000925226

RefSeq mRNA: 4 — MANE Select: NM_001080469 NM_001080469, NM_001329632, NM_001329633, NM_001329634

CCDS: CCDS46116

Canonical transcript exons

ENST00000317683 — 2 exons

Exon	Start	End
ENSE00001257370	45710629	45713573
ENSE00001779846	45730849	45730896

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 88.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.2970 / max 48.7361, expressed in 1692 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181559	4.6970	1663
181557	0.5772	325
181560	0.0155	3
181561	0.0073	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	88.69	gold quality
mucosa of transverse colon	UBERON:0004991	86.20	gold quality
esophagus mucosa	UBERON:0002469	85.64	gold quality
granulocyte	CL:0000094	83.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.55	gold quality
body of uterus	UBERON:0009853	82.92	gold quality
right ovary	UBERON:0002118	82.65	gold quality
ectocervix	UBERON:0012249	82.55	gold quality
esophagus	UBERON:0001043	82.51	gold quality
transverse colon	UBERON:0001157	82.44	gold quality
left ovary	UBERON:0002119	82.42	gold quality
esophagus squamous epithelium	UBERON:0006920	82.35	gold quality
blood	UBERON:0000178	82.32	gold quality
apex of heart	UBERON:0002098	82.03	gold quality
ganglionic eminence	UBERON:0004023	81.47	gold quality
body of stomach	UBERON:0001161	81.46	gold quality
embryo	UBERON:0000922	81.32	gold quality
choroid plexus epithelium	UBERON:0003911	81.30	silver quality
skin of leg	UBERON:0001511	81.09	gold quality
spleen	UBERON:0002106	81.01	gold quality
cortical plate	UBERON:0005343	80.86	gold quality
right lobe of thyroid gland	UBERON:0001119	80.76	gold quality
skin of abdomen	UBERON:0001416	80.72	gold quality
right uterine tube	UBERON:0001302	80.64	gold quality
ventricular zone	UBERON:0003053	80.28	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.11	gold quality
left uterine tube	UBERON:0001303	79.94	gold quality
right lobe of liver	UBERON:0001114	79.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.77

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• reveal that FBXO46 is a crucial proteasomal regulator of FBXO31 and thereby prevents senescence in normal growth conditions (PMID:30171069)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo46	ENSDARG00000099814
mus_musculus	Fbxo46	ENSMUSG00000050428
rattus_norvegicus	Fbxo46	ENSRNOG00000008815

Paralogs (1): FBXO34 (ENSG00000178974)

Protein

Protein identifiers

F-box only protein 46 — Q6PJ61 (reviewed: Q6PJ61)

Alternative names: F-box only protein 34-like

All UniProt accessions (3): Q6PJ61, K7EKF1, K7ERN4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF(FBXO46) protein ligase complex, which mediates the ubiquitination and degradation of target proteins. In absence of stress, the SCF(FBXO46) complex catalyzes ubiquitination and degradation of MTOR-phosphorylated FBXO31.

Subunit / interactions. Part of a SCF (SKP1-cullin-F-box) protein ligase complex SCF(FBXO46) composed of CUL1, SKP1, RBX1 and FBXO46.

Post-translational modifications. Phosphorylated by ATM in response to DNA damage, promoting ubiquitination and degradation by the SCF(FBXO31) complex. ATM-phosphorylated FBXO46 is ubiquitinated and degradaded by the SCF(FBXO31) complex in response to DNA damage.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (4): NP_001073938, NP_001316561, NP_001316562, NP_001316563 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR039594	FBXO34/46	Family

Pfam: PF12937

UniProt features (19 total): mutagenesis site 5, region of interest 5, modified residue 4, compositionally biased region 3, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PJ61-F1	45.48	0.01

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 (4): 21, 67, 338, 347

Mutagenesis-validated functional residues (5):

Position	Phenotype
21	decreased degradation in response to genotoxic stress.
67	decreased degradation in response to genotoxic stress.
216	does not affect interaction with fbxo31.
217	decreased interaction with fbxo31; when associated with 440-a–a-442.
440–442	decreased interaction with fbxo31; when associated with a-217.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GENTILE_UV_HIGH_DOSE_DN, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, MODULE_20, GENTILE_UV_RESPONSE_CLUSTER_D7, GOBP_PROTEIN_CATABOLIC_PROCESS, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, YAGI_AML_WITH_11Q23_REARRANGED, GOCC_TRANSFERASE_COMPLEX, LAIHO_COLORECTAL_CANCER_SERRATED_DN, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (1): SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (1): SCF ubiquitin ligase complex (GO:0019005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteasome-mediated ubiquitin-dependent protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO46	CUL1	Q13616	615
FBXO46	SKP1	P34991	585
FBXO46	KLHL29	Q96CT2	479
FBXO46	ASB6	Q9NWX5	464
FBXO46	CFAP68	Q9H5F2	445
FBXO46	POLR1F	Q3B726	438
FBXO46	THOC7	Q6I9Y2	422
FBXO46	CFAP92	Q9ULG3	419
FBXO46	FBXO42	Q6P3S6	402
FBXO46	FBXO38	Q6PIJ6	392
FBXO46	CEP57L1	Q8IYX8	390
FBXO46	RSPH6A	Q9H0K4	388
FBXO46	SNRPD2	P43330	388
FBXO46	LHFPL7	Q6ICI0	366
FBXO46	RRS1	Q15050	360

IntAct

29 interactions, top by confidence:

A	B	Type	Score
FBXO46	SKP1	psi-mi:“MI:0915”(physical association)	0.840
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
FBXO46	CYLD	psi-mi:“MI:0407”(direct interaction)	0.440
SKP1	FBXO46	psi-mi:“MI:0915”(physical association)	0.400
Skp1	XPO1	psi-mi:“MI:0914”(association)	0.350
MYO18A	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MYO1C	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MYO19	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Tmod3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Myh9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Myo1c	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Myh9	GOSR1	psi-mi:“MI:0914”(association)	0.350
Arrb2	TCOF1	psi-mi:“MI:0914”(association)	0.350
CAPZA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
NEXN	MYO1B	psi-mi:“MI:0914”(association)	0.350
SDC1	ARVCF	psi-mi:“MI:0914”(association)	0.350
COPS5	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
RNH1	DUSP11	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
SKP1	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
SKP1	NDC80	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS), FBXO46 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RR11, A0A0U1RRI6, A6NCS6, A6NJG2, B0BN44, D3YXK1, E9PY61, E9Q0B3, F5H4A9, O00220, O00221, P09038, P0DPI3, P22083, P98077, Q08AU9, Q2M2W7, Q2M3V2, Q2TBI2, Q5F267, Q5FW56, Q5IS69, Q5R866, Q5T4W7, Q5TM52, Q5U4P2, Q5VTJ3, Q659K9, Q673H1, Q69ZB3, Q6AYE8, Q6IPT2, Q6PJ61, Q7RTU4, Q7TSX9, Q7YR31, Q80SU3, Q86SH2, Q86Y97, Q8NBR0

Diamond homologs: Q4KLY2, Q6PJ61, Q80XI1, Q8BG80, Q9NWN3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

263 predictions. Top by Δscore:

Variant	Effect	Δscore
19:45730846:CAC:C	donor_loss	0.9900
19:45730847:A:AC	donor_gain	0.9900
19:45730848:C:CC	donor_gain	0.9900
19:45730816:T:A	donor_gain	0.9800
19:45730848:CCAT:C	donor_gain	0.9800
19:45713574:C:CG	acceptor_loss	0.9600
19:45713575:T:A	acceptor_loss	0.9600
19:45730835:G:A	donor_gain	0.9500
19:45730847:AC:A	donor_gain	0.9400
19:45730848:CC:C	donor_gain	0.9400
19:45713570:CCAC:C	acceptor_gain	0.9300
19:45713571:CACC:C	acceptor_gain	0.9300
19:45730869:C:CA	donor_gain	0.9100
19:45713574:C:CC	acceptor_gain	0.9000
19:45716754:A:AC	donor_gain	0.8900
19:45716755:C:CC	donor_gain	0.8900
19:45729799:G:C	donor_gain	0.8900
19:45717387:C:A	donor_gain	0.8700
19:45718206:AGGAC:A	donor_gain	0.8700
19:45713571:CAC:C	acceptor_gain	0.8500
19:45718205:CAGG:C	donor_gain	0.8500
19:45718206:AGGA:A	donor_gain	0.8500
19:45719664:A:C	donor_gain	0.8300
19:45730845:T:A	donor_gain	0.8300
19:45717349:C:A	donor_gain	0.8200
19:45713569:GCCAC:G	acceptor_gain	0.8000
19:45713570:CCACC:C	acceptor_gain	0.8000
19:45713581:C:CT	acceptor_gain	0.8000
19:45723902:A:T	acceptor_gain	0.7900
19:45730778:C:A	donor_gain	0.7900

AlphaMissense

3869 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:45711741:C:A	W585C	1.000
19:45711741:C:G	W585C	1.000
19:45711743:A:G	W585R	1.000
19:45711743:A:T	W585R	1.000
19:45711747:G:C	N583K	1.000
19:45711747:G:T	N583K	1.000
19:45711751:T:A	D582V	1.000
19:45711770:A:G	C576R	1.000
19:45711798:G:C	C566W	1.000
19:45711799:C:T	C566Y	1.000
19:45711800:A:G	C566R	1.000
19:45711801:G:C	C565W	1.000
19:45711802:C:T	C565Y	1.000
19:45711803:A:G	C565R	1.000
19:45711807:C:A	W563C	1.000
19:45711807:C:G	W563C	1.000
19:45711809:A:G	W563R	1.000
19:45711809:A:T	W563R	1.000
19:45711842:A:C	Y552D	1.000
19:45711846:C:A	K550N	1.000
19:45711846:C:G	K550N	1.000
19:45711852:G:C	H548Q	1.000
19:45711852:G:T	H548Q	1.000
19:45711853:T:C	H548R	1.000
19:45711854:G:C	H548D	1.000
19:45711855:C:A	W547C	1.000
19:45711855:C:G	W547C	1.000
19:45711857:A:G	W547R	1.000
19:45711857:A:T	W547R	1.000
19:45711861:G:C	C545W	1.000

dbSNP variants (sampled 300 via entrez): RS1000000521 (19:45731354 TCACCCAGG>T), RS1000011890 (19:45730054 T>A), RS1000033077 (19:45731034 G>A,T), RS1000079599 (19:45723978 G>A), RS1000569308 (19:45725768 G>A), RS1000595961 (19:45719410 A>G), RS1000652101 (19:45713319 G>T), RS1000710257 (19:45719769 C>T), RS1000819462 (19:45713550 G>A,T), RS1000947150 (19:45731643 A>G), RS1000987454 (19:45726308 C>T), RS1001010093 (19:45731942 C>T), RS1001038392 (19:45726095 A>C,G), RS1001047628 (19:45732594 T>C), RS1001077861 (19:45725439 A>C)

Disease associations

OMIM: gene MIM:609117 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001521_31	Subcutaneous adipose tissue	2.000000e-06
GCST001521_39	Subcutaneous adipose tissue	1.000000e-06
GCST004606_41	Eosinophil count	6.000000e-12
GCST007612_3	Chronic obstructive pulmonary disease or coronary artery disease (pleiotropy)	1.000000e-08
GCST90002384_457	Hemoglobin	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0004509	hemoglobin measurement

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	2
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Mifepristone	decreases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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