KBTBD12

Summary

KBTBD12 (kelch repeat and BTB domain containing 12, HGNC:25731) is a protein-coding gene on chromosome 3q21.3, encoding Kelch repeat and BTB domain-containing protein 12 (Q3ZCT8).

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm.

Source: NCBI Gene 166348 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 115 total
• Druggable target: yes
• MANE Select transcript: NM_207335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25731
Approved symbol	KBTBD12
Name	kelch repeat and BTB domain containing 12
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ46299
Ensembl gene	ENSG00000187715
Ensembl biotype	protein_coding
Entrez	166348

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000343941, ENST00000405109, ENST00000407609, ENST00000476626, ENST00000492025, ENST00000497045, ENST00000863455, ENST00000965238, ENST00000965239, ENST00000965240

RefSeq mRNA: 2 — MANE Select: NM_207335 NM_001370224, NM_207335

CCDS: CCDS33848

Canonical transcript exons

ENST00000405109 — 6 exons

Exon	Start	End
ENSE00001547256	127922950	127924131
ENSE00001552120	127984097	127987666
ENSE00001562436	127915232	127915586
ENSE00003482021	127930133	127930283
ENSE00003491450	127963189	127963386
ENSE00003503821	127927764	127928034

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 95.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6282 / max 61.0028, expressed in 167 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38414	0.2518	71
38415	0.1173	36
38412	0.0967	57
38411	0.0698	40
38413	0.0541	18
38417	0.0255	17
38416	0.0130	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	95.65	gold quality
quadriceps femoris	UBERON:0001377	95.48	gold quality
vastus lateralis	UBERON:0001379	95.30	gold quality
deltoid	UBERON:0001476	94.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.08	gold quality
skeletal muscle tissue	UBERON:0001134	93.45	gold quality
biceps brachii	UBERON:0001507	93.00	gold quality
pancreatic ductal cell	CL:0002079	92.43	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.46	gold quality
muscle of leg	UBERON:0001383	88.13	gold quality
muscle tissue	UBERON:0002385	87.59	gold quality
gastrocnemius	UBERON:0001388	87.38	gold quality
left ventricle myocardium	UBERON:0006566	86.69	gold quality
heart left ventricle	UBERON:0002084	83.64	gold quality
cardiac ventricle	UBERON:0002082	83.49	gold quality
apex of heart	UBERON:0002098	82.61	gold quality
heart right ventricle	UBERON:0002080	81.73	gold quality
oviduct epithelium	UBERON:0004804	80.28	gold quality
calcaneal tendon	UBERON:0003701	77.71	gold quality
heart	UBERON:0000948	76.47	gold quality
body of tongue	UBERON:0011876	76.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.84	gold quality
body of pancreas	UBERON:0001150	73.42	gold quality
tendon	UBERON:0000043	72.06	gold quality
epithelial cell of pancreas	CL:0000083	71.98	silver quality
mucosa of stomach	UBERON:0001199	71.48	gold quality
ventricular zone	UBERON:0003053	70.87	gold quality
rectum	UBERON:0001052	70.17	gold quality
descending thoracic aorta	UBERON:0002345	69.68	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	29.54
E-MTAB-7249	yes	27.22
E-ANND-3	yes	3.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

103 targeting KBTBD12, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kbtbd12	ENSDARG00000001882
mus_musculus	Kbtbd12	ENSMUSG00000033182
rattus_norvegicus	Kbtbd12	ENSRNOG00000061868

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

Kelch repeat and BTB domain-containing protein 12 — Q3ZCT8 (reviewed: Q3ZCT8)

Alternative names: Kelch domain-containing protein 6

All UniProt accessions (2): B5MCZ4, Q3ZCT8

Isoforms (2)

UniProt ID	Names	Canonical?
Q3ZCT8-1	1	yes
Q3ZCT8-2	2

RefSeq proteins (2): NP_001357153, NP_997218* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family

Pfam: PF00651, PF07707, PF24681

UniProt features (51 total): strand 31, turn 6, repeat 4, helix 3, domain 2, splice variant 2, chain 1, sequence conflict 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7QZQ	X-RAY DIFFRACTION	1.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3ZCT8-F1	90.16	0.73

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 68 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HNF1_Q6, GGCNKCCATNK_UNKNOWN, TCF4_Q5, YGACNNYACAR_UNKNOWN, WTGAAAT_UNKNOWN, TGACATY_UNKNOWN, HNF1_C, chr3q21, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, TGGAAA_NFAT_Q4_01, GOCC_TRANSFERASE_COMPLEX, RAAGNYNNCTTY_UNKNOWN, GOBP_PROTEOLYSIS

GO Biological Process (1): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

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

GO Cellular Component (2): cytoplasm (GO:0005737), Cul3-RING ubiquitin ligase complex (GO:0031463)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KBTBD12	PRR35	P0CG20	676
KBTBD12	RRP36	Q96EU6	589
KBTBD12	TMEM161B	Q8NDZ6	560
KBTBD12	TOGARAM1	Q9Y4F4	557
KBTBD12	SPMIP7	A4D263	554
KBTBD12	TAFA2	Q8N3H0	545
KBTBD12	TRAPPC6B	Q86SZ2	540
KBTBD12	IHO1	Q8IYA8	533
KBTBD12	KCNG3	Q8TAE7	529
KBTBD12	TMEM117	Q9H0C3	526
KBTBD12	SIPA1L2	Q9P2F8	523
KBTBD12	VWC2	Q2TAL6	521
KBTBD12	PKDCC	Q504Y2	507
KBTBD12	RAB11FIP3	O75154	493
KBTBD12	DECR2	Q9NUI1	492

IntAct

0 interactions, top by confidence:

BioGRID (3): KBTBD12 (Reconstituted Complex), KBTBD12 (Cross-Linking-MS (XL-MS)), WDR91 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1B8YAB1, B1H285, B3DIV9, E9QIN8, E9QJ30, F1QEG2, O88879, Q08CL3, Q08CY1, Q0D2A9, Q13939, Q28068, Q3UQV5, Q3ZCT8, Q503R4, Q5F3N5, Q5R4S6, Q5R663, Q5RG82, Q5XHZ6, Q5XI58, Q5ZI33, Q69ZK5, Q6DFF7, Q6DFU2, Q6Q7X9, Q6V595, Q7ZVQ8, Q86V97, Q8BHI4, Q8BUL5, Q8BWA5, Q8CA72, Q8CDE2, Q8CE33, Q8IXQ5, Q8NAB2, Q8NFY9, Q8R179, Q8WVZ9

Diamond homologs: A0A2R8Q1W5, A9JRD8, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, D3ZUU2, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, F1LZF0, F1MBP6, G3X9X1, O15062, O93567, O94889, O95198, P28575, P57790, Q04652, Q08DK3, Q13105, Q14145, Q16RL8, Q1ECZ2, Q2M0J9, Q2TBA0, Q3SWU4, Q3ZB90

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	109
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1307 predictions. Top by Δscore:

Variant	Effect	Δscore
3:127927835:G:GT	donor_gain	1.0000
3:127927835:G:T	donor_gain	1.0000
3:127927890:G:GG	donor_gain	1.0000
3:127927913:A:G	donor_gain	1.0000
3:127930130:CAGA:C	acceptor_loss	1.0000
3:127930131:AGAT:A	acceptor_gain	1.0000
3:127930132:GAT:G	acceptor_gain	1.0000
3:127930132:GATG:G	acceptor_gain	1.0000
3:127930225:G:GT	donor_gain	1.0000
3:127930233:C:CG	donor_gain	1.0000
3:127930233:C:G	donor_gain	1.0000
3:127930266:G:GG	donor_gain	1.0000
3:127984215:G:GT	donor_gain	1.0000
3:127925998:G:GT	donor_gain	0.9900
3:127927909:GTTGA:G	donor_gain	0.9900
3:127927910:TTGAT:T	donor_gain	0.9900
3:127927913:A:AG	donor_gain	0.9900
3:127930121:T:G	acceptor_gain	0.9900
3:127930131:A:AG	acceptor_gain	0.9900
3:127930131:AGATG:A	acceptor_gain	0.9900
3:127930132:G:GA	acceptor_gain	0.9900
3:127930132:GATGG:G	acceptor_gain	0.9900
3:127930236:A:AG	donor_gain	0.9900
3:127930237:G:GG	donor_gain	0.9900
3:127930280:TTGG:T	donor_loss	0.9900
3:127930281:TGGG:T	donor_loss	0.9900
3:127930282:GG:G	donor_gain	0.9900
3:127930283:GG:G	donor_gain	0.9900
3:127930283:GGTAA:G	donor_loss	0.9900
3:127930284:G:A	donor_loss	0.9900

AlphaMissense

4136 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:127923218:A:C	S53R	0.999
3:127923220:C:A	S53R	0.999
3:127923220:C:G	S53R	0.999
3:127984153:T:A	W583R	0.999
3:127984153:T:C	W583R	0.999
3:127923953:A:C	S298R	0.998
3:127923955:T:A	S298R	0.998
3:127923955:T:G	S298R	0.998
3:127930205:T:A	W472R	0.998
3:127930205:T:C	W472R	0.998
3:127927865:G:A	G391E	0.997
3:127923662:T:A	W201R	0.996
3:127923662:T:C	W201R	0.996
3:127923863:C:A	R268S	0.996
3:127923896:T:C	C279R	0.996
3:127927789:T:A	W366R	0.996
3:127927789:T:C	W366R	0.996
3:127963275:T:A	W527R	0.996
3:127963275:T:C	W527R	0.996
3:127923383:G:C	A108P	0.995
3:127927868:G:A	G392E	0.995
3:127928018:G:A	G442E	0.995
3:127930184:T:G	Y465D	0.995
3:127963254:T:G	Y520D	0.995
3:127963365:T:C	C557R	0.995
3:127984124:T:A	I573K	0.995
3:127984201:T:C	C599R	0.995
3:127923723:G:C	R221T	0.994
3:127928021:G:A	G443D	0.994
3:127930207:G:C	W472C	0.994

dbSNP variants (sampled 300 via entrez): RS1000001390 (3:127932233 T>A), RS1000067220 (3:127948855 A>G), RS1000140105 (3:127947942 A>G), RS1000212187 (3:127919882 T>A,C), RS1000225778 (3:127969176 T>C), RS1000247782 (3:127956714 G>A), RS1000278347 (3:127968831 G>T), RS1000309604 (3:127955114 C>A,T), RS1000368769 (3:127970908 T>A), RS1000410088 (3:127962210 C>T), RS1000425105 (3:127987575 G>A), RS1000440697 (3:127914385 A>C,G), RS1000471829 (3:127914292 T>A,C), RS1000483285 (3:127915379 G>A), RS1000521653 (3:127949252 G>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (1): primary amenorrhea (MONDO:1060208)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007611_8	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	9.000000e-10
GCST90002402_325	Platelet count	9.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196097 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
FR900359	increases phosphorylation	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
abrine	increases expression	1
Arsenic	decreases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Nickel	decreases expression	1
Valproic Acid	decreases methylation	1
Cadmium Chloride	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6094277	Binding	Binding affinity to KBTBD12 (unknown origin) at 10 uM by thermal shift assay	Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice