KLHL20

Summary

KLHL20 (kelch like family member 20, HGNC:25056) is a protein-coding gene on chromosome 1q25.1, encoding Kelch-like protein 20 (Q9Y2M5). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in interferon response and anterograde Golgi to endosome transport.

The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities.

Source: NCBI Gene 27252 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 86 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• MANE Select transcript: NM_014458

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25056
Approved symbol	KLHL20
Name	kelch like family member 20
Location	1q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KLEIP, KHLHX
Ensembl gene	ENSG00000076321
Ensembl biotype	protein_coding
OMIM	617679
Entrez	27252

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000209884, ENST00000479505, ENST00000483154, ENST00000488983, ENST00000493170, ENST00000875485, ENST00000875486, ENST00000875487, ENST00000875488, ENST00000945315

RefSeq mRNA: 1 — MANE Select: NM_014458 NM_014458

CCDS: CCDS1310

Canonical transcript exons

ENST00000209884 — 12 exons

Exon	Start	End
ENSE00000451350	173775634	173775842
ENSE00000789885	173751764	173751922
ENSE00000789886	173753213	173753307
ENSE00000789887	173755923	173756038
ENSE00000789888	173756976	173757159
ENSE00000789889	173766146	173766289
ENSE00000789890	173774305	173774438
ENSE00000789892	173782124	173782230
ENSE00000814654	173733713	173734286
ENSE00001329962	173785163	173786692
ENSE00001929248	173714981	173715078
ENSE00003670659	173716003	173716066

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2212 / max 155.1186, expressed in 1788 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6737	11.0961	1787
6738	0.1251	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.12	gold quality
calcaneal tendon	UBERON:0003701	91.26	gold quality
oocyte	CL:0000023	91.02	gold quality
tendon	UBERON:0000043	90.67	gold quality
tendon of biceps brachii	UBERON:0008188	89.77	gold quality
sperm	CL:0000019	89.40	gold quality
male germ cell	CL:0000015	88.57	gold quality
blood vessel layer	UBERON:0004797	86.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.35	gold quality
nipple	UBERON:0002030	85.90	gold quality
popliteal artery	UBERON:0002250	85.75	gold quality
tibial artery	UBERON:0007610	85.75	gold quality
artery	UBERON:0001637	85.43	gold quality
ventricular zone	UBERON:0003053	85.32	gold quality
gall bladder	UBERON:0002110	85.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.16	gold quality
aorta	UBERON:0000947	84.99	gold quality
right coronary artery	UBERON:0001625	84.99	gold quality
stromal cell of endometrium	CL:0002255	84.91	gold quality
smooth muscle tissue	UBERON:0001135	84.87	gold quality
descending thoracic aorta	UBERON:0002345	84.78	gold quality
muscle of leg	UBERON:0001383	84.66	gold quality
colonic epithelium	UBERON:0000397	84.57	gold quality
urethra	UBERON:0000057	84.50	gold quality
ganglionic eminence	UBERON:0004023	84.48	gold quality
pericardium	UBERON:0002407	84.35	gold quality
gastrocnemius	UBERON:0001388	84.32	gold quality
cortical plate	UBERON:0005343	84.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.12	gold quality
thoracic aorta	UBERON:0001515	84.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

134 targeting KLHL20, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-MIR-4533	100.00	69.48	2758
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1468-3P	99.96	72.74	3797

Literature-anchored findings (GeneRIF, showing 8)

• BTB-kelch protein KLEIP, a novel regulator of endothelial function during angiogenesis, controls the vascular endothelial growth factor (VEGF)-induced activation of Rho GTPases. (PMID:17395875)
• KLHL20-Cul3-ROC1 is an E3 ligase for DAPK ubiquitination (PMID:20389280)
• study indicates that the KLHL20-mediated PML degradation and HIF-1alpha autoregulation play key roles in tumor progression (PMID:21840486)
• These results indicate that KLHL20 is a novel player that regulates HIF-2alpha protein expression through mechanisms independent of hypoxia and pVHL. (PMID:21888897)
• study reveals a function of KLHL20-mediated, K33-linked ubiquitination of Crn7 in the assembly of (trans-Golgi network )TGN-associated F-actin to promote post-Golgi trafficking and identifies a cellular decoding mechanism for this ubiquitin chain type. (PMID:24768539)
• Study identifies a key role of Cul3-KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism. (PMID:26687681)
• A 1.1-A degrees crystal structure of a KLHL20-DAPK1 complex reveals a hydrophobic pocket in KLHL20. DAPK1 helical turn inserts into the beta-propeller to contact all six Kelch repeats of KLHL20. (PMID:31279627)
• De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder. (PMID:36214804)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl20	ENSDARG00000038801
mus_musculus	Klhl20	ENSMUSG00000026705
rattus_norvegicus	Klhl20	ENSRNOG00000002875
drosophila_melanogaster	dbo	FBGN0040230
caenorhabditis_elegans	kel-20	WBGENE00020030

Paralogs (54): KLHL13 (ENSG00000003096), 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), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 20 — Q9Y2M5 (reviewed: Q9Y2M5)

Alternative names: Kelch-like ECT2-interacting protein, Kelch-like protein X

All UniProt accessions (1): Q9Y2M5

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in interferon response and anterograde Golgi to endosome transport. The BCR(KLHL20) E3 ubiquitin ligase complex mediates the ubiquitination of DAPK1, leading to its degradation by the proteasome, thereby acting as a negative regulator of apoptosis. The BCR(KLHL20) E3 ubiquitin ligase complex also specifically mediates ‘Lys-33’-linked ubiquitination. Involved in anterograde Golgi to endosome transport by mediating ‘Lys-33’-linked ubiquitination of CORO7, promoting interaction between CORO7 and EPS15, thereby facilitating actin polymerization and post-Golgi trafficking. Also acts as a regulator of endothelial migration during angiogenesis by controlling the activation of Rho GTPases. The BCR(KLHL20) E3 ubiquitin ligase complex acts as a regulator of neurite outgrowth by mediating ubiquitination and degradation of PDZ-RhoGEF/ARHGEF11. In case of tumor, the BCR(KLHL20) E3 ubiquitin ligase complex is involved in tumor hypoxia: following hypoxia, the BCR(KLHL20)complex mediates ubiquitination and degradation of PML, potentiating HIF-1 signaling and cancer progression.

Subunit / interactions. Component of the BCR(KLHL20) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL20 and RBX1. Interacts with PDZ-RhoGEF/ARHGEF11, DAPK1, PML and CORO7. Interacts with F-actin. Interacts with IFN-gamma (IFNG). Interacts (via kelch repeats) with IVNS1ABP (via kelch repeats); this interaction blocks the assembly of CUL3-KLHL20 complex.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus. Golgi apparatus. trans-Golgi network. Cell projection. Axon. Dendrite.

Induction. By hypoxia.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2M5-1	1	yes
Q9Y2M5-2	2

RefSeq proteins (1): NP_055273* (*=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 (55 total): strand 27, mutagenesis site 6, turn 6, repeat 6, sequence conflict 5, domain 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6GY5	X-RAY DIFFRACTION	1.09
5YQ4	X-RAY DIFFRACTION	1.58
8CIA	X-RAY DIFFRACTION	3.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2M5-F1	88.51	0.75

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 (6):

Position	Phenotype
109	in klhl20m6; abolishes interaction with cul3; when associated with a-111; a-113; a-146; a-148 and a-150.
111	in klhl20m6; abolishes interaction with cul3; when associated with a-109; a-113; a-146; a-148 and a-150.
113	in klhl20m6; abolishes interaction with cul3; when associated with a-109; a-111; a-146; a-148 and a-150.
146	in klhl20m6; abolishes interaction with cul3; when associated with a-109; a-111; a-113; a-148 and a-150.
148	in klhl20m6; abolishes interaction with cul3; when associated with a-109; a-111; a-113; a-146 and a-150.
150	in klhl20m6; abolishes interaction with cul3; when associated with a-109; a-111; a-113; a-146 and a-148.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 216 (showing top): GCACCTT_MIR18A_MIR18B, RRAGTTGT_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, TGCACTT_MIR519C_MIR519B_MIR519A, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AACYNNNNTTCCS_UNKNOWN, GOBP_VESICLE_MEDIATED_TRANSPORT, AAAYRNCTG_UNKNOWN, GOBP_RESPONSE_TO_INTERFERON_ALPHA

GO Biological Process (8): Golgi to endosome transport (GO:0006895), cytoskeleton organization (GO:0007010), protein transport (GO:0015031), protein ubiquitination (GO:0016567), response to interferon-alpha (GO:0035455), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein K33-linked ubiquitination (GO:1990390)

GO Molecular Function (5): actin binding (GO:0003779), ubiquitin-protein transferase activity (GO:0004842), type II interferon binding (GO:0019964), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (12): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), PML body (GO:0016605), axon (GO:0030424), dendrite (GO:0030425), Cul3-RING ubiquitin ligase complex (GO:0031463), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
intracellular membrane-bounded organelle	2
neuron projection	2
post-Golgi vesicle-mediated transport	1
intercellular transport	1
cytosolic transport	1
organelle organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
protein modification by small protein conjugation	1
response to cytokine	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein polyubiquitination	1
cytoskeletal protein binding	1
ubiquitin-like protein transferase activity	1
interferon binding	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
Golgi apparatus subcompartment	1
cytoskeleton	1
nuclear body	1
dendritic tree	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL20	CUL3	Q13618	995
KLHL20	RBX1	P62877	872
KLHL20	DAPK1	P53355	794
KLHL20	ASB7	Q9H672	636
KLHL20	PIK3C3	Q8NEB9	634
KLHL20	CORO7	P57737	633
KLHL20	ASB13	Q8WXK3	631
KLHL20	ARIH2	O95376	612
KLHL20	BECN1	Q14457	582
KLHL20	A0A0A6YYL4	A0A0A6YYL4	546
KLHL20	RNF4	P78317	539
KLHL20	ST13	P50502	533
KLHL20	EPAS1	Q99814	500
KLHL20	KLHDC2	Q9Y2U9	493
KLHL20	CUL2	Q13617	492

IntAct

227 interactions, top by confidence:

A	B	Type	Score
CUL3	KLHL20	psi-mi:“MI:0915”(physical association)	0.920
KLHL20	CUL3	psi-mi:“MI:0914”(association)	0.920
CUL3	KLHL20	psi-mi:“MI:0407”(direct interaction)	0.920
CUL3	KLHL20	psi-mi:“MI:0914”(association)	0.920
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
PML	KLHL20	psi-mi:“MI:0915”(physical association)	0.810
PML	KLHL20	psi-mi:“MI:0403”(colocalization)	0.810
KLHL20	PML	psi-mi:“MI:0407”(direct interaction)	0.810
KLHL20	PML	psi-mi:“MI:0914”(association)	0.810
KLHL20	PML	psi-mi:“MI:0915”(physical association)	0.810
KLHL20	DAPK1	psi-mi:“MI:0914”(association)	0.780
KLHL20	DAPK1	psi-mi:“MI:0915”(physical association)	0.780
KLHL20	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.780
KLHL24	CUL3	psi-mi:“MI:0914”(association)	0.730
FBXL17	BACH1	psi-mi:“MI:0914”(association)	0.730
HOOK3	FHIP1A	psi-mi:“MI:0914”(association)	0.710
RELB	NFKBIE	psi-mi:“MI:0914”(association)	0.670
KLHL20	MECP2	psi-mi:“MI:0915”(physical association)	0.670
KLHL20	PML	psi-mi:“MI:0915”(physical association)	0.660
KLHL20	PML	psi-mi:“MI:0914”(association)	0.660
KLHL20	PML	psi-mi:“MI:0407”(direct interaction)	0.660
KLHL20	IVNS1ABP	psi-mi:“MI:0915”(physical association)	0.650
KLHL20	IVNS1ABP	psi-mi:“MI:0407”(direct interaction)	0.650

BioGRID (331): ARHGEF12 (Biochemical Activity), FCGR3B (Affinity Capture-MS), SATB2 (Affinity Capture-MS), NUFIP2 (Affinity Capture-MS), MAP7D2 (Affinity Capture-MS), USP27X (Affinity Capture-MS), SPAG7 (Affinity Capture-MS), EIF2S2 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS), HDGFRP2 (Affinity Capture-MS), MIOS (Affinity Capture-MS), NARS (Affinity Capture-MS), ATXN2L (Affinity Capture-MS), FBXL17 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS)

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: A0A1B8YAB1, A1YPR0, B0WWP2, B1H285, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D3Z8N4, E0CZ16, G3X9X1, O15062, O88939, O93567, O95365, P28575, P41182, P41183, Q08CL3, Q08DK3, Q13105, Q16RL8, Q2M0J9, Q3UQV5, Q52KB5, Q5EXX3, Q5R7B8, Q5RDY3, Q5TC79, Q5ZI33, Q5ZKD9, Q5ZM39, Q60821

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
KLHL20	“down-regulates quantity by destabilization”	DAPK1	binding
KLHL20	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
KLHL20	“down-regulates quantity by destabilization”	ULK1	binding
KLHL20	“down-regulates quantity by destabilization”	PIK3C3	binding
KLHL20	“down-regulates quantity by destabilization”	BECN1	binding
KLHL20	“up-regulates activity”	“Cullin 3-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	6	20.2×	3e-04
adult locomotory behavior	6	17.7×	4e-04
protein destabilization	5	14.2×	4e-03
protein autoubiquitination	6	13.8×	1e-03
negative regulation of neuron apoptotic process	8	8.7×	1e-03
kidney development	6	8.3×	9e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	15	7.7×	1e-06
protein ubiquitination	11	4.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	61
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
4294324	NM_014458.4(KLHL20):c.1214G>A (p.Ser405Asn)	Pathogenic
4294325	NM_014458.4(KLHL20):c.1262A>G (p.Gln421Arg)	Pathogenic
4294326	NM_014458.4(KLHL20):c.1777G>T (p.Gly593Trp)	Pathogenic
4294327	NM_014458.4(KLHL20):c.1636G>A (p.Gly546Arg)	Pathogenic
3535064	NM_014458.4(KLHL20):c.1219G>C (p.Gly407Arg)	Likely pathogenic
4076511	NM_014458.4(KLHL20):c.629C>G (p.Pro210Arg)	Likely pathogenic

SpliceAI

1694 predictions. Top by Δscore:

Variant	Effect	Δscore
1:173733701:T:G	acceptor_gain	1.0000
1:173733703:A:AG	acceptor_gain	1.0000
1:173733704:T:G	acceptor_gain	1.0000
1:173733710:TA:T	acceptor_loss	1.0000
1:173733711:A:AC	acceptor_loss	1.0000
1:173733711:AGGT:A	acceptor_gain	1.0000
1:173733712:GGT:G	acceptor_gain	1.0000
1:173733712:GGTG:G	acceptor_gain	1.0000
1:173733712:GGTGT:G	acceptor_gain	1.0000
1:173734152:G:GT	donor_gain	1.0000
1:173751752:A:AG	acceptor_gain	1.0000
1:173751753:A:G	acceptor_gain	1.0000
1:173751900:A:T	donor_gain	1.0000
1:173751920:CAGGT:C	donor_loss	1.0000
1:173751921:AGG:A	donor_loss	1.0000
1:173751923:G:T	donor_loss	1.0000
1:173751924:T:A	donor_loss	1.0000
1:173753211:A:AG	acceptor_gain	1.0000
1:173753212:G:GG	acceptor_gain	1.0000
1:173756023:G:T	donor_gain	1.0000
1:173756974:A:AG	acceptor_gain	1.0000
1:173756974:AGTT:A	acceptor_gain	1.0000
1:173756975:G:GA	acceptor_gain	1.0000
1:173756975:GTTG:G	acceptor_gain	1.0000
1:173775632:A:AG	acceptor_gain	1.0000
1:173775633:G:GG	acceptor_gain	1.0000
1:173775838:GTGGA:G	donor_gain	1.0000
1:173775839:TGGA:T	donor_gain	1.0000
1:173775840:GGA:G	donor_gain	1.0000
1:173775840:GGAG:G	donor_gain	1.0000

AlphaMissense

3977 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:173733874:G:C	R62T	1.000
1:173733895:A:T	D69V	1.000
1:173733904:T:C	L72P	1.000
1:173733937:G:C	R83P	1.000
1:173733946:T:C	L86S	1.000
1:173733946:T:G	L86W	1.000
1:173733957:A:C	S90R	1.000
1:173733959:T:A	S90R	1.000
1:173733959:T:G	S90R	1.000
1:173733963:T:C	Y92H	1.000
1:173733967:T:C	F93S	1.000
1:173733976:T:C	M96T	1.000
1:173733977:G:A	M96I	1.000
1:173733977:G:C	M96I	1.000
1:173733977:G:T	M96I	1.000
1:173733978:T:C	F97L	1.000
1:173733979:T:C	F97S	1.000
1:173733980:T:A	F97L	1.000
1:173733980:T:G	F97L	1.000
1:173733998:G:C	E103D	1.000
1:173733998:G:T	E103D	1.000
1:173734054:T:C	L122P	1.000
1:173734062:T:C	F125L	1.000
1:173734064:T:A	F125L	1.000
1:173734064:T:G	F125L	1.000
1:173734111:T:C	L141P	1.000
1:173734114:T:A	L142Q	1.000
1:173734114:T:C	L142P	1.000
1:173734120:C:A	A144D	1.000
1:173734122:G:C	A145P	1.000

dbSNP variants (sampled 300 via entrez): RS1000008836 (1:173749335 A>G,T), RS1000011048 (1:173728750 G>A), RS1000072978 (1:173777028 A>G), RS1000092575 (1:173726599 G>A), RS1000115791 (1:173715778 A>G), RS1000116178 (1:173778457 T>C), RS1000162299 (1:173726259 G>A,T), RS1000221245 (1:173778199 C>G), RS1000274157 (1:173769142 G>C), RS1000286827 (1:173762443 A>C), RS1000308995 (1:173742124 T>C), RS1000373693 (1:173763560 T>C), RS1000491618 (1:173770909 A>T), RS1000547956 (1:173726452 T>G), RS1000553863 (1:173776635 A>G)

Disease associations

OMIM: gene MIM:617679 | disease phenotypes: MIM:621390

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Moderate	AD

Mondo (5): prostate cancer (MONDO:0008315), neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities (MONDO:0980709), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Familial prostate cancer (Orphanet:1331), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000098	Tall stature
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000243	Trigonocephaly
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000321	Square face
HP:0000329	Facial hemangioma
HP:0000347	Micrognathia
HP:0000350	Small forehead
HP:0000400	Macrotia
HP:0000414	Bulbous nose
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000582	Upslanted palpebral fissure
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000767	Pectus excavatum
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001332	Dystonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006943_60	Feeling miserable	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009598	feeling miserable measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067461 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.22	Kd	600	nM	CHEMBL5613204

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(5R,11S,14S,17S,20R)-5-amino-20-carbamoyl-17-(2-methylpropyl)-6,12,15,18-tetraoxo-3,22-dithia-7,13,16,19-tetrazatricyclo[22.3.1.07,11]octacosa-1(28),24,26-trien-14-yl]acetic acid	2124197: Binding affinity to KLHL20 (unknown origin) assessed as dissociation constant by fluorescence polarization assay	kd	0.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
salinomycin	decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
NSC 689534	affects binding, increases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Copper	increases expression, affects binding	1
Dexamethasone	increases expression	1
Diethylstilbestrol	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Oxygen	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases methylation	1
Valproic Acid	decreases expression	1
Vitamin E	affects cotreatment, decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5608438	Binding	Binding affinity to KLHL20 (unknown origin) 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 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9I2	Ubigene HEK293 KLHL20 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery