KLHL12

Summary

KLHL12 (kelch like family member 12, HGNC:19360) is a protein-coding gene on chromosome 1q32.1, encoding Kelch-like protein 12 (Q53G59). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport.

This gene encodes a member of the KLHL (Kelch-like) family of proteins. This protein has been identified as an autoantigen in the autoimmune disease Sjogren’s syndrome and as a potential biomarker in primary biliary cirrhosis. This protein may act as a substrate adaptor of the Cullin-3 ubiquitin ligase complex to promote substrate-specific ubiquitylation. Ubiquitylation by this complex has been shown to regulate the Wnt signaling pathway as well as COPII vesicle coat size. A pseudogene has been identified on chromosome 22. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 59349 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total
• Druggable target: yes
• MANE Select transcript: NM_021633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19360
Approved symbol	KLHL12
Name	kelch like family member 12
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	C3IP1
Ensembl gene	ENSG00000117153
Ensembl biotype	protein_coding
OMIM	614522
Entrez	59349

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000367258, ENST00000367259, ENST00000367261, ENST00000870805, ENST00000870806, ENST00000870807, ENST00000870808, ENST00000870809, ENST00000870810, ENST00000941773, ENST00000941774

RefSeq mRNA: 3 — MANE Select: NM_021633 NM_001303051, NM_001303109, NM_021633

CCDS: CCDS1429

Canonical transcript exons

ENST00000367261 — 12 exons

Exon	Start	End
ENSE00001648475	202891120	202892659
ENSE00001674920	202895522	202895717
ENSE00001714574	202894184	202894282
ENSE00001758216	202893239	202893425
ENSE00001758834	202896854	202896960
ENSE00001791048	202894591	202894749
ENSE00001835443	202927089	202927234
ENSE00002278923	202911054	202911203
ENSE00002287507	202919755	202919908
ENSE00002318794	202918171	202918388
ENSE00003588113	202924968	202925207
ENSE00003787312	202909010	202909124

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 95.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4841 / max 225.8831, expressed in 1815 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16750	21.2251	1815
16749	0.2453	76
16751	0.0137	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.89	gold quality
secondary oocyte	CL:0000655	94.75	gold quality
ileal mucosa	UBERON:0000331	94.50	gold quality
left ventricle myocardium	UBERON:0006566	94.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.98	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.73	gold quality
middle temporal gyrus	UBERON:0002771	92.97	gold quality
kidney epithelium	UBERON:0004819	92.25	gold quality
sperm	CL:0000019	91.66	gold quality
ventricular zone	UBERON:0003053	91.65	gold quality
right testis	UBERON:0004534	91.55	gold quality
esophagus squamous epithelium	UBERON:0006920	91.30	gold quality
islet of Langerhans	UBERON:0000006	91.26	gold quality
testis	UBERON:0000473	91.05	gold quality
tibialis anterior	UBERON:0001385	91.01	gold quality
left testis	UBERON:0004533	90.87	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.70	gold quality
ganglionic eminence	UBERON:0004023	90.17	gold quality
upper arm skin	UBERON:0004263	89.70	gold quality
rectum	UBERON:0001052	89.61	gold quality
prefrontal cortex	UBERON:0000451	89.48	gold quality
adult organism	UBERON:0007023	89.34	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.76	gold quality
deltoid	UBERON:0001476	88.73	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.70	gold quality
colonic mucosa	UBERON:0000317	88.65	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.61	gold quality
hypothalamus	UBERON:0001898	88.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting KLHL12, 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-511-3P	99.99	68.85	1467
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-6794-3P	98.76	66.99	894

Literature-anchored findings (GeneRIF, showing 7)

• molecular cloning and characterization of a novel gene, encoded a human kelch protein containing 568 amino acid residues, termed hDKIR. (PMID:15383316)
• KLHL12 specifically interacts with the D4 polymorphism, thereby building up a Cul3-E3 ligase complex with substrate specificity toward the D4 receptor (PMID:18303015)
• KLHL12 promotes ubiquitination of the dopamine D4 receptor on non-lysine residues. (PMID:26717573)
• p44/42 MAPK phosphorylation, the signaling pathway which is often regulated by beta-arrestins is not influenced by KLHL12, but seems to be exclusively mediated by Galphai protein upon dopamine D4 receptor stimulation. (PMID:27155323)
• The interaction between the KLHL12 and the C-terminal domain of KHSRP contributed to KHSRP ubiquitination, leading to downregulation of enterovirus internal ribosome entry sites-mediated translation in infected cells. (PMID:27899653)
• Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3(KLHL12) Ubiquitin Ligase Complex. (PMID:32433973)
• Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12. (PMID:32574548)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	KLHL12	ENSDARG00000112728
mus_musculus	Klhl12	ENSMUSG00000026455
rattus_norvegicus	Klhl12	ENSRNOG00000004193
drosophila_melanogaster	kel	FBGN0001301
caenorhabditis_elegans		WBGENE00002184

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), 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), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 12 — Q53G59 (reviewed: Q53G59)

Alternative names: CUL3-interacting protein 1, DKIR homolog

All UniProt accessions (3): Q53G59, J3QSX3, Q9H7R2

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport. The BCR(KLHL12) complex is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B). The BCR(KLHL12) complex is also involved in neural crest specification: in response to cytosolic calcium increase, interacts with the heterodimer formed with PEF1 and PDCD6/ALG-2, leading to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export. As part of the BCR(KLHL12) complex, also acts as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of DVL3. The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins.

Subunit / interactions. Component of the BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL12 and RBX1. This complex interacts with DVL3 upon activation of the Wnt signaling pathway by WNT3A. Interacts with DRD4, KLHL2 and SEC31A. Interacts with PEF1 and PDCD6/ALG-2; interaction takes place in response to cytosolic calcium increase and leads to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B).

Subcellular location. Cytoplasmic vesicle. COPII-coated vesicle.

Tissue specificity. Ubiquitously expressed. Highly expressed in testis and at lower levels in the submandibular salivary gland.

Post-translational modifications. Ubiquitinated by the SCF(FBXL17) complex, leading to its degradation by the proteasome: ubiquitination by the SCF(FBXL17) complex takes place when aberrant BTB domain dimers are formed.

Domain organisation. The BTB domain is required for interaction with CUL3.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q53G59-1	1	yes
Q53G59-2	2

RefSeq proteins (3): NP_001289980, NP_001290038, NP_067646* (*=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, PF01344, PF07707, PF24681

UniProt features (53 total): strand 27, turn 6, repeat 6, mutagenesis site 5, sequence conflict 3, domain 2, chain 1, splice variant 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
9Y8U	X-RAY DIFFRACTION	1.01
9Y8Q	X-RAY DIFFRACTION	1.2
9Y8K	X-RAY DIFFRACTION	1.27
9Y8L	X-RAY DIFFRACTION	1.27
9Y8V	X-RAY DIFFRACTION	1.27
9Y8O	X-RAY DIFFRACTION	1.29
9Y8S	X-RAY DIFFRACTION	1.29
9Y8N	X-RAY DIFFRACTION	1.31
9Y8M	X-RAY DIFFRACTION	1.33
9Y8R	X-RAY DIFFRACTION	1.33
9Y8T	X-RAY DIFFRACTION	1.4
2VPJ	X-RAY DIFFRACTION	1.85
8RBH	X-RAY DIFFRACTION	1.88
8OIO	X-RAY DIFFRACTION	1.95
6TTK	X-RAY DIFFRACTION	2.38
9Y8J	X-RAY DIFFRACTION	2.7
6V7O	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53G59-F1	93.39	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (5):

Position	Phenotype
15	abolished ubiquitination by the scf(fbxl17) complex.
34	abolished ubiquitination by the scf(fbxl17) complex.
50	increased recognition and ubiquitination by the scf(fbxl17) complex.
60	abolished ubiquitination by the scf(fbxl17) complex.
289–290	abolishes interaction with sec31a and subsequent monoubiquitination of sec31a. abolishes ubiquitination of pef1.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-4641258	Degradation of DVL
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 169 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GCM_GSPT1, GOBP_VESICLE_LOCALIZATION, GOBP_VESICLE_ORGANIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VESICLE_TARGETING, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, GOCC_COATED_VESICLE, GOBP_PROTEIN_MONOUBIQUITINATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOCC_VESICLE_COAT, CREB_Q2_01, DOUGLAS_BMI1_TARGETS_DN

GO Biological Process (11): protein monoubiquitination (GO:0006513), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), neural crest formation (GO:0014029), neural crest cell development (GO:0014032), Wnt signaling pathway (GO:0016055), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), COPII vesicle coat assembly (GO:0048208), anatomical structure morphogenesis (GO:0009653), tissue development (GO:0009888), vesicle-mediated transport (GO:0016192), protein ubiquitination (GO:0016567)

GO Molecular Function (3): identical protein binding (GO:0042802), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), COPII vesicle coat (GO:0030127), COPII-coated ER to Golgi transport vesicle (GO:0030134), Cul3-RING ubiquitin ligase complex (GO:0031463), centriolar satellite (GO:0034451), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
anatomical structure development	2
protein ubiquitination	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
epithelial to mesenchymal transition	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
neural crest cell differentiation	1
stem cell development	1
cell surface receptor signaling pathway	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
vesicle coat assembly	1
protein-containing complex assembly	1
COPII-coated vesicle budding	1
developmental process	1
transport	1
cellular process	1
protein modification by small protein conjugation	1
protein binding	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
ER to Golgi transport vesicle membrane	1
vesicle coat	1
coated vesicle	1
cullin-RING ubiquitin ligase complex	1
centrosome	1
intracellular vesicle	1

Protein interactions and networks

STRING

1346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL12	CUL3	Q13618	982
KLHL12	PEF1	Q9UBV8	882
KLHL12	PLEKHA4	Q9H4M7	696
KLHL12	MIA3	Q5JRA6	624
KLHL12	MIA2	Q96PC5	613
KLHL12	SEC31A	O94979	594
KLHL12	TRAPPC2	P0DI81	590
KLHL12	SEC13	P55735	526
KLHL12	TXNL1	O43396	518
KLHL12	SEC16A	O15027	489
KLHL12	SEC24D	O94855	465
KLHL12	SEC24B	O95487	458
KLHL12	CIDEB	Q9UHD4	453
KLHL12	ALG2	Q9H553	449
KLHL12	NUP210	Q8TEM1	447

IntAct

360 interactions, top by confidence:

A	B	Type	Score
KLHL12	CUL3	psi-mi:“MI:0915”(physical association)	0.920
CUL3	KLHL12	psi-mi:“MI:0915”(physical association)	0.920
KLHL12	PEF1	psi-mi:“MI:0915”(physical association)	0.880
PEF1	KLHL12	psi-mi:“MI:0915”(physical association)	0.880
KLHL12	KLHL12	psi-mi:“MI:0915”(physical association)	0.860
SDCBP	KLHL12	psi-mi:“MI:0915”(physical association)	0.790
NTAQ1	KLHL12	psi-mi:“MI:0915”(physical association)	0.790
KLHL12	SDCBP	psi-mi:“MI:0915”(physical association)	0.790
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
PRR13	KLHL12	psi-mi:“MI:0915”(physical association)	0.780
KLHL12	PRR13	psi-mi:“MI:0915”(physical association)	0.780
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
KLHL12	INMT	psi-mi:“MI:0915”(physical association)	0.720
PDGFRB	KLHL12	psi-mi:“MI:0915”(physical association)	0.720
KLHL12	FLNA	psi-mi:“MI:0915”(physical association)	0.720
KLHL12	MPP1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (273): KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), KLHL12 (Two-hybrid), ZBP1 (Two-hybrid)

ESM2 similar proteins: A0A2R8Q1W5, A6QQY2, B0WWP2, B3NDN0, B4HIK1, B4L0G9, B4LIG6, B4PD06, D3Z8N4, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, O94889, P28575, P57790, P59280, Q08DK3, Q14145, Q16RL8, Q2T9Z7, Q53G59, Q5R774, Q5R7B8, Q5U374, Q5ZKD9, Q5ZLD3, Q684M4, Q6DFF6, Q6JEL2, Q6JEL3, Q6NRH0, Q6TDP3, Q6TDP4, Q6ZPT1, Q7QGL0, Q80TF4, Q8BZM0, Q8K430

Diamond homologs: A0A0A6YY25, B2RXH4, E0CZ16, E1B932, E7F6F9, F1LZ52, F1LZF0, F1MBP6, O88282, O93567, O95198, P10074, P17789, P42282, P42283, P42284, Q01295, Q1H9T6, Q24174, Q24206, Q3B7M1, Q52KG4, Q53G59, Q53HC5, Q5R633, Q5REP9, Q5U374, Q66HD2, Q6NRH0, Q7KQZ4, Q7KRI2, Q867Z4, Q86B87, Q8BGY4, Q8BZM0, Q8CA72, Q8IN81, Q8JZP3, Q8K0L9, Q8N143

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
KLHL12	“down-regulates quantity by destabilization”	DVL1	binding
KLHL12	“up-regulates activity”	SEC31A	binding
KLHL12	“up-regulates activity”	“Cullin 3-RBX1-Skp1”	binding
KLHL12	“up-regulates activity”	SEC31B	binding
KLHL12	“up-regulates activity”	LNPK	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Neddylation	12	10.5×	3e-07
Cargo recognition for clathrin-mediated endocytosis	5	9.7×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein neddylation	5	45.6×	4e-05
positive regulation of JNK cascade	5	10.6×	5e-03
regulation of actin cytoskeleton organization	5	10.2×	6e-03
ubiquitin-dependent protein catabolic process	9	8.7×	2e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	11	7.5×	7e-05
protein ubiquitination	11	5.9×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2101 predictions. Top by Δscore:

Variant	Effect	Δscore
1:202893237:AC:A	donor_gain	1.0000
1:202893238:CC:C	donor_gain	1.0000
1:202893286:G:C	donor_gain	1.0000
1:202893304:A:AC	donor_gain	1.0000
1:202893305:C:CC	donor_gain	1.0000
1:202894177:GTCTT:G	donor_loss	1.0000
1:202894178:TCTTA:T	donor_loss	1.0000
1:202894179:CTTAC:C	donor_loss	1.0000
1:202894180:TTACC:T	donor_loss	1.0000
1:202894181:TACC:T	donor_loss	1.0000
1:202894182:A:AC	donor_gain	1.0000
1:202894183:C:CC	donor_gain	1.0000
1:202894183:C:T	donor_loss	1.0000
1:202894586:AATAC:A	donor_gain	1.0000
1:202894588:TA:T	donor_loss	1.0000
1:202894589:ACC:A	donor_loss	1.0000
1:202894590:C:G	donor_loss	1.0000
1:202894594:G:C	donor_gain	1.0000
1:202894608:C:CA	donor_gain	1.0000
1:202894635:T:TA	donor_gain	1.0000
1:202894636:C:A	donor_gain	1.0000
1:202894745:CATAT:C	acceptor_gain	1.0000
1:202894747:TAT:T	acceptor_gain	1.0000
1:202894747:TATCT:T	acceptor_loss	1.0000
1:202894749:TCT:T	acceptor_loss	1.0000
1:202894750:C:CA	acceptor_loss	1.0000
1:202894750:C:CC	acceptor_gain	1.0000
1:202894751:T:G	acceptor_loss	1.0000
1:202894755:C:CT	acceptor_gain	1.0000
1:202895596:T:C	donor_gain	1.0000

AlphaMissense

3731 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:202892599:C:A	W547C	1.000
1:202892599:C:G	W547C	1.000
1:202892601:A:G	W547R	1.000
1:202892601:A:T	W547R	1.000
1:202893239:C:A	G527V	1.000
1:202893239:C:T	G527E	1.000
1:202893240:C:G	G527R	1.000
1:202893240:C:T	G527R	1.000
1:202893321:A:G	W500R	1.000
1:202893321:A:T	W500R	1.000
1:202893376:A:C	F481L	1.000
1:202893376:A:T	F481L	1.000
1:202893378:A:G	F481L	1.000
1:202893380:C:T	G480E	1.000
1:202893383:C:T	G479E	1.000
1:202893384:C:A	G479W	1.000
1:202894190:G:T	R463S	1.000
1:202894220:A:G	W453R	1.000
1:202894220:A:T	W453R	1.000
1:202894279:C:T	G433E	1.000
1:202894282:C:T	G432E	1.000
1:202894667:C:A	W406C	1.000
1:202894667:C:G	W406C	1.000
1:202894668:C:G	W406S	1.000
1:202894669:A:G	W406R	1.000
1:202894669:A:T	W406R	1.000
1:202894690:A:C	Y399D	1.000
1:202894719:C:T	G389E	1.000
1:202894724:A:C	F387L	1.000
1:202894724:A:T	F387L	1.000

dbSNP variants (sampled 300 via entrez): RS1000031395 (1:202898320 T>C), RS1000236243 (1:202923488 G>A,C), RS1000531286 (1:202897990 T>C), RS1000681649 (1:202924627 A>G), RS1000721342 (1:202909413 T>C), RS1000730396 (1:202917277 C>T), RS1000780872 (1:202923029 G>A), RS1000853075 (1:202902979 G>A), RS1000988255 (1:202902617 A>G), RS1000993731 (1:202921090 A>G), RS1001131534 (1:202896399 C>T), RS1001185719 (1:202910759 A>G,T), RS1001201103 (1:202930380 C>G,T), RS1001290163 (1:202921911 C>T), RS1001396020 (1:202905476 G>A,T)

Disease associations

OMIM: gene MIM:614522 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066235 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, affects cotreatment, increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	affects expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	increases expression, affects cotreatment	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases expression	1
Cadmium Chloride	increases expression, increases abundance	1
Acrylamide	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5608434	Binding	Binding affinity to KLHL12 (unknown origin) extracted from Escherichia coli BL21 Gold (DE3) assessed as dissociation constant by fluorescence polarization assay	Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8NV	Ubigene HCT 116 KLHL12 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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