FBXW12

Summary

FBXW12 (F-box and WD repeat domain containing 12, HGNC:20729) is a protein-coding gene on chromosome 3p21.31, encoding F-box/WD repeat-containing protein 12 (Q6X9E4). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Members of the F-box protein family, such as FBXW12, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603034), 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 285231 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 72 total
• MANE Select transcript: NM_207102

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20729
Approved symbol	FBXW12
Name	F-box and WD repeat domain containing 12
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	Fbw12
Ensembl gene	ENSG00000164049
Ensembl biotype	protein_coding
OMIM	609075
Entrez	285231

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000296438, ENST00000415155, ENST00000436231, ENST00000445170, ENST00000468158, ENST00000477542

RefSeq mRNA: 3 — MANE Select: NM_207102 NM_001159927, NM_001159929, NM_207102

CCDS: CCDS2764, CCDS54577, CCDS54578

Canonical transcript exons

ENST00000296438 — 11 exons

Exon	Start	End
ENSE00001367820	48373548	48373705
ENSE00001372687	48381700	48381878
ENSE00001372875	48373308	48373345
ENSE00001382345	48372684	48372857
ENSE00001385993	48381955	48382085
ENSE00001409694	48394560	48394725
ENSE00002720728	48372219	48372320
ENSE00003544399	48379400	48379558
ENSE00003590194	48380702	48380912
ENSE00003604134	48375354	48375472
ENSE00003684616	48378317	48378526

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 80.39.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	80.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.71	silver quality
pancreas	UBERON:0001264	65.51	gold quality
ventricular zone	UBERON:0003053	62.15	gold quality
cerebellar cortex	UBERON:0002129	58.73	gold quality
cerebellar hemisphere	UBERON:0002245	58.73	gold quality
right uterine tube	UBERON:0001302	58.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	58.16	gold quality
cerebellum	UBERON:0002037	57.46	gold quality
right frontal lobe	UBERON:0002810	55.41	gold quality
amygdala	UBERON:0001876	54.80	gold quality
prefrontal cortex	UBERON:0000451	54.62	gold quality
anterior cingulate cortex	UBERON:0009835	54.59	gold quality
Brodmann (1909) area 9	UBERON:0013540	54.19	gold quality
nucleus accumbens	UBERON:0001882	53.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	52.59	silver quality
neocortex	UBERON:0001950	52.53	gold quality
right lobe of liver	UBERON:0001114	52.47	gold quality
metanephros cortex	UBERON:0010533	52.35	gold quality
caudate nucleus	UBERON:0001873	52.33	gold quality
frontal cortex	UBERON:0001870	52.19	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	51.50	gold quality
putamen	UBERON:0001874	51.49	gold quality
oocyte	CL:0000023	51.47	gold quality
cortical plate	UBERON:0005343	51.45	gold quality
lower esophagus mucosa	UBERON:0035834	51.00	gold quality
adult mammalian kidney	UBERON:0000082	50.92	gold quality
brain	UBERON:0000955	50.88	gold quality
cerebral cortex	UBERON:0000956	50.88	gold quality
Ammon’s horn	UBERON:0001954	50.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.96

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• FBXO35 gene had a ubiquitously low expression pattern in most human adult tissues. FBXO35 gene was found located in chromosome 3p21. (PMID:15040455)
• FBXW12 functions as an E3 ligase constituent to ubiquitinate and degrade IL-22R and that therapeutic FBXW12 inhibition may enhance IL-22 signaling and bolster mucosal host defense and infection containment. (PMID:26171402)
• FBXW12 gene is deleted in approximately ten percent of the epithelial ovarian cancer cases studied; such deletions comprised either the FBXW12 promoter or the mRNA-encoding region. (PMID:26617728)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr54	ENSDARG00000010248
danio_rerio	si:dkey-202c14.3	ENSDARG00000096532
danio_rerio	si:ch211-154o6.3	ENSDARG00000099846
mus_musculus	Fbxw21	ENSMUSG00000047237
mus_musculus	Fbxw13	ENSMUSG00000049314
mus_musculus	Fbxw28	ENSMUSG00000054087
mus_musculus	Fbxw26	ENSMUSG00000059547
mus_musculus	Fbxw20	ENSMUSG00000061701
mus_musculus	Fbxw24	ENSMUSG00000062275
mus_musculus	Fbxw22	ENSMUSG00000070324
mus_musculus	Fbxw18	ENSMUSG00000074059
mus_musculus	Fbxw15	ENSMUSG00000074060
mus_musculus	Fbxw19	ENSMUSG00000074061
mus_musculus	Fbxw16	ENSMUSG00000074062
mus_musculus	Fbxw25	ENSMUSG00000094992
mus_musculus	Fbxw27	ENSMUSG00000104614
mus_musculus	Fbxw14	ENSMUSG00000105589
rattus_norvegicus	Fbxw12	ENSRNOG00000020720
drosophila_melanogaster	WDY	FBGN0267449
caenorhabditis_elegans		WBGENE00004744
caenorhabditis_elegans		WBGENE00004767

Paralogs (14): WDR54 (ENSG00000005448), FBXW11 (ENSG00000072803), FBXW7 (ENSG00000109670), TRAF7 (ENSG00000131653), FBXW9 (ENSG00000132004), FBXO36 (ENSG00000153832), WDR64 (ENSG00000162843), BTRC (ENSG00000166167), WDR49 (ENSG00000174776), FBXW8 (ENSG00000174989), PAAF1 (ENSG00000175575), WDR86 (ENSG00000187260), FBXO16 (ENSG00000214050), EFCAB8 (ENSG00000215529)

Protein

Protein identifiers

F-box/WD repeat-containing protein 12 — Q6X9E4 (reviewed: Q6X9E4)

Alternative names: F-box and WD-40 domain-containing protein 12, F-box only protein 35

All UniProt accessions (2): C9JK86, Q6X9E4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Promotes degradation of interleukin-22 receptor subunit IL22RA1 in resting and IL22-stimulated conditions by facilitating its ubiquitination. Functions as a cell growth suppressor.

Subunit / interactions. Interacts with SKP1. Interacts with CUL1. Interacts with IL22RA1.

Tissue specificity. Ubiquitously expressed.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6X9E4-1	1	yes
Q6X9E4-2	2
Q6X9E4-3	3

RefSeq proteins (3): NP_001153399, NP_001153401, NP_996985* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR011044	Quino_amine_DH_bsu	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR052121	F-box_SCF_Substrate_Recog	Family

Pfam: PF12937

UniProt features (17 total): repeat 8, sequence variant 3, splice variant 2, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6X9E4-F1	88.24	0.61

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 57 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, AFFAR_YY1_TARGETS_DN, SCHLINGEMANN_SKIN_CARCINOGENESIS_TPA_UP, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, GOCC_TRANSFERASE_COMPLEX, MARSON_BOUND_BY_FOXP3_STIMULATED, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (1): protein ubiquitination (GO:0016567)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein modification by small protein conjugation	1
binding	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXW12	SKP1	P34991	656
FBXW12	CUL1	Q13616	633
FBXW12	FBXW9	Q5XUX1	544
FBXW12	FBXW4	P57775	488
FBXW12	FBXW10	Q5XX13	475
FBXW12	FBXL13	Q8NEE6	475
FBXW12	FBXW5	Q969U6	463
FBXW12	FBXW2	Q9UKT8	460
FBXW12	TAS2R9	Q9NYW1	458
FBXW12	FBXW8	Q8N3Y1	454
FBXW12	FBXW11	Q9UKB1	448
FBXW12	C5orf52	A6NGY3	448
FBXW12	CFAP97D1	B2RV13	439
FBXW12	FBXO41	Q8TF61	423
FBXW12	FBXO34	Q9NWN3	400

IntAct

2 interactions, top by confidence:

A	B	Type	Score
FBXW12	RUNX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): IL22RA1 (Affinity Capture-Western), SKP1 (Affinity Capture-Western), IL22RA1 (Biochemical Activity), FBXW12 (Affinity Capture-MS), FBXW12 (Synthetic Lethality), GET4 (Affinity Capture-MS), RUNX2 (Affinity Capture-MS), FAM63A (Affinity Capture-MS), RUNX1 (Affinity Capture-MS), RUNX3 (Affinity Capture-MS), CBFB (Affinity Capture-MS), MAP3K7 (Affinity Capture-Western), FBXW12 (Co-fractionation), FBXW12 (Co-fractionation)

ESM2 similar proteins: A0A1L8GXY4, A4D1P6, A8XSV3, B0JZ65, B0R160, B0WYR6, E9Q7R9, F1REV3, F6S215, O00443, O65418, P50748, Q09178, Q12769, Q17I16, Q19317, Q2TAW0, Q3MHH2, Q402B2, Q4V9P9, Q5R6T6, Q5RAY1, Q5RB52, Q5RE88, Q5ZJY3, Q5ZL79, Q5ZLL7, Q6DTM3, Q6GM71, Q6INI5, Q6P996, Q6X9E4, Q6ZQQ6, Q7TMQ7, Q86XI2, Q8BJW5, Q8BMQ2, Q8C3Y4, Q8K3E5, Q8N157

Diamond homologs: A1C7E4, A1DHW6, A2QCU8, B0XTS1, B6Q4Z5, B8M7Q5, B8NGT5, D4AM37, D4D8P3, L7N1X6, P87053, Q0CY32, Q2UFN8, Q4X0A9, Q6X9E4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FBXW12	“down-regulates quantity by destabilization”	IL22RA1	binding
FBXW12	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1613 predictions. Top by Δscore:

Variant	Effect	Δscore
3:48373641:G:GT	donor_gain	1.0000
3:48373642:A:T	donor_gain	1.0000
3:48373690:G:GG	donor_gain	1.0000
3:48381676:T:G	acceptor_gain	1.0000
3:48381678:T:G	acceptor_gain	1.0000
3:48381690:A:AG	acceptor_gain	1.0000
3:48381690:AT:A	acceptor_gain	1.0000
3:48381691:T:G	acceptor_gain	1.0000
3:48373306:A:AG	acceptor_gain	0.9900
3:48373307:G:GG	acceptor_gain	0.9900
3:48373614:G:GT	donor_gain	0.9900
3:48373729:GAACA:G	donor_gain	0.9900
3:48381672:T:G	acceptor_gain	0.9900
3:48381674:T:G	acceptor_gain	0.9900
3:48381689:C:G	acceptor_gain	0.9900
3:48373711:GGTA:G	donor_gain	0.9800
3:48375352:A:AG	acceptor_gain	0.9800
3:48375353:G:GG	acceptor_gain	0.9800
3:48378315:AG:A	acceptor_gain	0.9800
3:48378316:GG:G	acceptor_gain	0.9800
3:48381660:T:G	acceptor_gain	0.9800
3:48381675:ATAT:A	acceptor_gain	0.9800
3:48381677:ATGT:A	acceptor_gain	0.9800
3:48381678:T:TA	acceptor_gain	0.9800
3:48381682:C:CA	acceptor_gain	0.9800
3:48381688:A:AG	acceptor_gain	0.9800
3:48381688:ACAT:A	acceptor_gain	0.9800
3:48381699:GC:G	acceptor_gain	0.9800
3:48381789:A:AG	acceptor_gain	0.9800
3:48381790:G:GG	acceptor_gain	0.9800

AlphaMissense

3081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:48380792:T:A	W289R	0.989
3:48380792:T:C	W289R	0.989
3:48381717:T:C	F335L	0.985
3:48381719:C:A	F335L	0.985
3:48381719:C:G	F335L	0.985
3:48378335:A:C	S142R	0.984
3:48378337:C:A	S142R	0.984
3:48378337:C:G	S142R	0.984
3:48378428:T:A	W173R	0.983
3:48378428:T:C	W173R	0.983
3:48373311:T:A	W32R	0.980
3:48373311:T:C	W32R	0.980
3:48379517:T:A	W245R	0.976
3:48379517:T:C	W245R	0.976
3:48380794:G:C	W289C	0.976
3:48380794:G:T	W289C	0.976
3:48382008:G:C	W406C	0.976
3:48382008:G:T	W406C	0.976
3:48382006:T:A	W406R	0.974
3:48382006:T:C	W406R	0.974
3:48394591:A:C	S443R	0.971
3:48394593:C:A	S443R	0.971
3:48394593:C:G	S443R	0.971
3:48378329:T:A	W140R	0.970
3:48378329:T:C	W140R	0.970
3:48381802:T:C	L363S	0.970
3:48373341:T:A	W42R	0.969
3:48373341:T:C	W42R	0.969
3:48378430:G:C	W173C	0.968
3:48378430:G:T	W173C	0.968

dbSNP variants (sampled 300 via entrez): RS1000033582 (3:48380690 T>C), RS1000089258 (3:48388822 C>G), RS1000284416 (3:48374019 T>C), RS1000284554 (3:48372032 A>C,G), RS1000378133 (3:48394148 T>C), RS1000410751 (3:48393916 C>T), RS1000831832 (3:48370818 TTTG>T,TTTGTTG), RS1000989204 (3:48394721 T>G), RS1001040493 (3:48378454 G>A), RS1001050639 (3:48381031 T>G), RS1001143396 (3:48381255 C>G), RS1001327616 (3:48390468 G>A), RS1001406681 (3:48387710 G>A,C,T), RS1001770321 (3:48371150 T>C), RS1002297357 (3:48377545 G>T)

Disease associations

OMIM: gene MIM:609075 | 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
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17080138	FBXW12		0.00	0

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	decreases expression	1
lead acetate	affects cotreatment, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
zinc protoporphyrin	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Formaldehyde	increases expression	1
Glucose	increases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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