FBXL12

Summary

FBXL12 (F-box and leucine rich repeat protein 12, HGNC:13611) is a protein-coding gene on chromosome 19p13.2, encoding F-box/LRR-repeat protein 12 (Q9NXK8). 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 FBXL12, 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 54850 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_017703

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13611
Approved symbol	FBXL12
Name	F-box and leucine rich repeat protein 12
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20188, Fbl12
Ensembl gene	ENSG00000127452
Ensembl biotype	protein_coding
OMIM	609079
Entrez	54850

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 3 nonsense_mediated_decay

ENST00000247977, ENST00000585379, ENST00000586073, ENST00000586469, ENST00000586651, ENST00000588922, ENST00000589438, ENST00000589626, ENST00000590277, ENST00000590808, ENST00000591009, ENST00000592067, ENST00000592732

RefSeq mRNA: 8 — MANE Select: NM_017703 NM_001316936, NM_001316937, NM_001316938, NM_001316939, NM_001316940, NM_001316941, NM_001316942, NM_017703

CCDS: CCDS12218, CCDS82287

Canonical transcript exons

ENST00000247977 — 3 exons

Exon	Start	End
ENSE00002846182	9818728	9819079
ENSE00003485708	9818545	9818617
ENSE00003668351	9810270	9811717

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 96.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.9866 / max 151.9060, expressed in 1811 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179035	11.5196	1793
179034	8.3560	1779
179036	1.0910	687
179033	0.0200	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	96.57	gold quality
pancreatic ductal cell	CL:0002079	89.80	gold quality
mucosa of transverse colon	UBERON:0004991	89.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.60	gold quality
ileal mucosa	UBERON:0000331	89.26	gold quality
left uterine tube	UBERON:0001303	89.23	gold quality
apex of heart	UBERON:0002098	88.82	gold quality
tibialis anterior	UBERON:0001385	88.75	gold quality
type B pancreatic cell	CL:0000169	88.70	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.68	gold quality
lower esophagus	UBERON:0013473	88.65	gold quality
olfactory bulb	UBERON:0002264	88.62	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.57	gold quality
right ovary	UBERON:0002118	88.51	gold quality
blood vessel layer	UBERON:0004797	88.46	gold quality
right coronary artery	UBERON:0001625	88.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.25	gold quality
mucosa of stomach	UBERON:0001199	88.15	gold quality
left ovary	UBERON:0002119	88.05	gold quality
thoracic aorta	UBERON:0001515	87.98	gold quality
aorta	UBERON:0000947	87.96	gold quality
popliteal artery	UBERON:0002250	87.96	gold quality
oocyte	CL:0000023	87.94	gold quality
tibial artery	UBERON:0007610	87.94	gold quality
body of uterus	UBERON:0009853	87.92	gold quality
ascending aorta	UBERON:0001496	87.90	gold quality
transverse colon	UBERON:0001157	87.72	gold quality
descending thoracic aorta	UBERON:0002345	87.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.42	gold quality
stromal cell of endometrium	CL:0002255	87.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

40 targeting FBXL12, 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-4283	100.00	66.42	2097
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-8075	99.97	67.20	962
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-670-3P	99.03	68.88	2404

Literature-anchored findings (GeneRIF, showing 4)

• Fbxl12-induced CaMKI degradation attenuates p27 phosphorylation at these sites in early G1 and iii) activation of CaMKI during G1 transition followed by p27 phosphorylation appears to be upstream to other p27 phosphorylation events (PMID:23707388)
• FBXL12 plays a key role in the down-regulation of ALDH3 activity in trophoblast stem cells and thus initiates trophoblast differentiation during placental development. (PMID:26124079)
• Study found that Fbl12 binds and ubiquitinates p21 which allows its stability. In addition, Fbl12 regulates default degradation under basal conditions but not under UV-stimulated conditions. These findings elucidate novel mechanisms that underlie the regulation of p21 expression level in cells. (PMID:27215384)
• FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress. (PMID:37591242)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fbxl12	ENSMUSG00000066892
rattus_norvegicus	Fbxl12	ENSRNOG00000064355

Protein

Protein identifiers

F-box/LRR-repeat protein 12 — Q9NXK8 (reviewed: Q9NXK8)

Alternative names: F-box and leucine-rich repeat protein 12, F-box protein FBL12

All UniProt accessions (10): Q9NXK8, K7EIK3, K7EIR3, K7EK37, K7ELM5, K7EPN7, K7EPT3, K7EQJ7, K7EQY7, K7ESL6

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Mediates the polyubiquitination and proteasomal degradation of CAMK1 leading to disruption of cyclin D1/CDK4 complex assembly which results in G1 cell cycle arrest in lung epithelia.

Subunit / interactions. Interacts with SKP1 and CUL1.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NXK8-1	1	yes
Q9NXK8-2	2

RefSeq proteins (8): NP_001303865, NP_001303866, NP_001303867, NP_001303868, NP_001303869, NP_001303870, NP_001303871, NP_060173* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily

Pfam: PF12937

UniProt features (12 total): repeat 8, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXK8-F1	88.95	0.69

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: 151 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, chr19p13

GO Biological Process (2): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567)

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

GO Cellular Component (3): ubiquitin ligase complex (GO:0000151), 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 ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1033 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL12	SKP1	P34991	845
FBXL12	CUL1	Q13616	804
FBXL12	FBXW8	Q8N3Y1	539
FBXL12	FBXL5	Q9UKA1	524
FBXL12	FBXO24	O75426	521
FBXL12	FBXL14	Q8N1E6	505
FBXL12	FBXL6	Q8N531	479
FBXL12	PRAME	P78395	476
FBXL12	FBXO4	Q9UKT5	469
FBXL12	UBL5	Q9BZL1	455
FBXL12	ZNF846	Q147U1	452
FBXL12	CAMK1	Q14012	447
FBXL12	PIK3R2	O00459	435
FBXL12	FBXL13	Q8NEE6	420
FBXL12	ERGIC3	Q9Y282	419

IntAct

69 interactions, top by confidence:

A	B	Type	Score
SKP1	FBXL12	psi-mi:“MI:0915”(physical association)	0.840
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
DOCK8	FBXL12	psi-mi:“MI:0915”(physical association)	0.560
LNX1	FBXL12	psi-mi:“MI:0915”(physical association)	0.560
FBXL12	DOCK8	psi-mi:“MI:0915”(physical association)	0.560
FBXL12	LNX1	psi-mi:“MI:0915”(physical association)	0.560
SKP1	FBXL12	psi-mi:“MI:0915”(physical association)	0.560
FBXL12	SKP1	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	FBXL12	psi-mi:“MI:0915”(physical association)	0.560
	PLOD2	psi-mi:“MI:0914”(association)	0.530
RNF32	FBXL12	psi-mi:“MI:0407”(direct interaction)	0.530
RNF32	FBXL12	psi-mi:“MI:0915”(physical association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
CDKN1C	FBXL12	psi-mi:“MI:0915”(physical association)	0.520
FBXL12	CDKN1C	psi-mi:“MI:0915”(physical association)	0.520
FBXL12	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
DOCK8	FBXL12	psi-mi:“MI:0915”(physical association)	0.370
FBF1	FBXL12	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (100): DOCK8 (Two-hybrid), LNX1 (Two-hybrid), ALDH3A1 (Affinity Capture-MS), ALDH3A2 (Affinity Capture-MS), RNH1 (Affinity Capture-MS), ANXA2 (Affinity Capture-MS), GSTP1 (Affinity Capture-MS), HGH1 (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), CAPN2 (Affinity Capture-MS), SLA (Affinity Capture-MS), RCN1 (Affinity Capture-MS), CBWD3 (Affinity Capture-MS), TTC27 (Affinity Capture-MS), ASTN2 (Affinity Capture-MS)

ESM2 similar proteins: A1A5X2, A2RT62, A6H639, A8Y3R9, B3FL73, D3Z902, D3ZXS4, G5EDB9, O49286, P34284, P87053, Q09299, Q0P4D1, Q0VD31, Q17R01, Q19857, Q32PG9, Q4R642, Q570C0, Q5BJ29, Q5JU00, Q5MJ12, Q65XV2, Q8BFZ4, Q8BH70, Q8BID8, Q8BVU0, Q8C4V4, Q8CDU4, Q8CFJ9, Q8J2J3, Q8LB33, Q8N1E6, Q8N461, Q8W104, Q96S15, Q9EPX5, Q9LPL4, Q9LW29, Q9NXK8

Diamond homologs: A1A5X2, Q13309, Q5BJ29, Q6PB97, Q6PCT2, Q9EPX5, Q9NXK8, Q9QZN1, Q9UJT9, Q9Z0Z3, A6H779, Q32PG9, Q5R3Z8, Q8BH16, Q9UKC9, A8QGZ7, B3FL73, Q3ZBA7, Q5NBU5, Q66H10, Q7Z6M2, Q8BFZ4, Q8C4V4, Q8VE08, Q9UKT6, Q9UKT7, P34284, Q5XGI3, Q6INS1, Q7TPD1, Q7TSL3, Q86XK2, Q8N531, Q8N4B4

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FBXL12	“down-regulates quantity”	CAMK1	ubiquitination
FBXL12	“down-regulates quantity by destabilization”	ALDH3A1	binding
FBXL12	“down-regulates quantity by destabilization”	ALDH3A2	binding
FBXL12	“down-regulates quantity by destabilization”	ALDH3B1	binding
FBXL12	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Potential therapeutics for SARS	5	12.2×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

487 predictions. Top by Δscore:

Variant	Effect	Δscore
19:9818616:CC:C	acceptor_gain	1.0000
19:9818617:CC:C	acceptor_gain	1.0000
19:9818722:CCGCA:C	donor_loss	1.0000
19:9818723:CGCA:C	donor_loss	1.0000
19:9818724:GCAC:G	donor_loss	1.0000
19:9818725:CACCT:C	donor_loss	1.0000
19:9818726:ACC:A	donor_loss	1.0000
19:9818727:C:A	donor_loss	1.0000
19:9811713:CGCAT:C	acceptor_gain	0.9900
19:9811715:CAT:C	acceptor_gain	0.9900
19:9811716:AT:A	acceptor_gain	0.9900
19:9811717:TCT:T	acceptor_loss	0.9900
19:9811718:C:CA	acceptor_loss	0.9900
19:9811718:C:CC	acceptor_gain	0.9900
19:9811719:T:G	acceptor_loss	0.9900
19:9818539:GCGTA:G	donor_loss	0.9900
19:9818540:CGTA:C	donor_loss	0.9900
19:9818541:GTACC:G	donor_loss	0.9900
19:9818542:TA:T	donor_loss	0.9900
19:9818543:ACCG:A	donor_loss	0.9900
19:9818544:C:CA	donor_loss	0.9900
19:9818613:AGACC:A	acceptor_gain	0.9900
19:9818618:C:CC	acceptor_gain	0.9900
19:9818618:C:T	acceptor_gain	0.9900
19:9811714:GCAT:G	acceptor_gain	0.9800
19:9811715:CATC:C	acceptor_gain	0.9800
19:9811728:C:CT	acceptor_gain	0.9800
19:9811728:C:T	acceptor_gain	0.9800
19:9818543:A:AC	donor_gain	0.9800
19:9818544:C:CC	donor_gain	0.9800

AlphaMissense

2077 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:9818574:A:G	W44R	0.998
19:9818574:A:T	W44R	0.998
19:9811476:C:T	C134Y	0.997
19:9818604:A:G	W34R	0.997
19:9818604:A:T	W34R	0.997
19:9811475:G:C	C134W	0.996
19:9811576:A:G	C101R	0.996
19:9818572:C:A	W44C	0.996
19:9818572:C:G	W44C	0.996
19:9811386:A:G	F164S	0.995
19:9811485:A:G	L131P	0.995
19:9811557:A:G	L107P	0.995
19:9811566:A:G	L104P	0.995
19:9811335:A:G	L181P	0.994
19:9811500:A:C	L126W	0.994
19:9811692:A:G	L62P	0.994
19:9818573:C:G	W44S	0.994
19:9811477:A:G	C134R	0.993
19:9811491:A:G	L129P	0.993
19:9811656:A:G	L74P	0.993
19:9811509:G:C	P123R	0.992
19:9811551:A:G	L109P	0.992
19:9818564:A:T	V47D	0.992
19:9818743:C:G	R24P	0.992
19:9811557:A:T	L107H	0.991
19:9811665:A:T	L71H	0.991
19:9811017:A:G	L287P	0.990
19:9811107:A:G	L257P	0.990
19:9811371:A:G	L169P	0.990
19:9811395:A:T	V161D	0.990

dbSNP variants (sampled 300 via entrez): RS1000378821 (19:9814530 T>A,C), RS1000424959 (19:9813823 G>A,C), RS1000771870 (19:9816636 C>T), RS1000828791 (19:9820244 A>G,T), RS1000854056 (19:9814889 T>C), RS1000881073 (19:9820537 T>C), RS1001140407 (19:9816380 C>A,T), RS1001868977 (19:9813537 T>C), RS1002133561 (19:9810926 G>A), RS1002467050 (19:9812183 C>T), RS1002852513 (19:9818273 G>A), RS1003156293 (19:9819144 T>C,G), RS1003749700 (19:9818633 C>T), RS1004145033 (19:9813796 C>T), RS1004422966 (19:9821042 C>T)

Disease associations

OMIM: gene MIM:609079 | 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
GCST005024_110	Pursuit maintenance gain	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008433	pursuit maintenance gain measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Air Pollutants, Occupational	affects expression	1
Asbestos	affects expression	1
Vehicle Emissions	increases abundance, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Sodium Selenite	increases expression	1
Lactic Acid	affects expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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