KLHDC2

Summary

KLHDC2 (kelch domain containing 2, HGNC:20231) is a protein-coding gene on chromosome 14q21.3, encoding Kelch domain-containing protein 2 (Q9Y2U9). Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation.

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nuclear body and nuclear membrane. Is active in Cul2-RING ubiquitin ligase complex and nucleus.

Source: NCBI Gene 23588 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 79 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_014315

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20231
Approved symbol	KLHDC2
Name	kelch domain containing 2
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	HCLP-1, LCP
Ensembl gene	ENSG00000165516
Ensembl biotype	protein_coding
OMIM	611280
Entrez	23588

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000298307, ENST00000553538, ENST00000553579, ENST00000553703, ENST00000554115, ENST00000554589, ENST00000555443, ENST00000555739, ENST00000556559, ENST00000557063, ENST00000557247, ENST00000893243, ENST00000893244, ENST00000913008

RefSeq mRNA: 1 — MANE Select: NM_014315 NM_014315

CCDS: CCDS9693

Canonical transcript exons

ENST00000298307 — 13 exons

Exon	Start	End
ENSE00001093723	49779595	49779675
ENSE00001093727	49768153	49768621
ENSE00001093728	49782830	49786385
ENSE00001093731	49779748	49779806
ENSE00003471051	49778178	49778259
ENSE00003489480	49777839	49777954
ENSE00003499840	49782542	49782594
ENSE00003505271	49771594	49771673
ENSE00003526773	49782370	49782457
ENSE00003552487	49778411	49778494
ENSE00003580617	49780703	49780775
ENSE00003594102	49780213	49780322
ENSE00003666493	49774561	49774678

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8626 / max 224.5924, expressed in 1811 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139448	24.1519	1805
139446	1.6118	1021
139449	1.1476	717
139447	0.7240	443
139444	0.4423	202
139445	0.4025	195
139451	0.2488	120
139450	0.0988	20
139452	0.0348	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.51	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.47	gold quality
calcaneal tendon	UBERON:0003701	98.43	gold quality
adult organism	UBERON:0007023	97.97	gold quality
body of pancreas	UBERON:0001150	97.91	gold quality
cardia of stomach	UBERON:0001162	97.84	gold quality
renal medulla	UBERON:0000362	97.82	gold quality
pons	UBERON:0000988	97.78	gold quality
pylorus	UBERON:0001166	97.77	gold quality
vastus lateralis	UBERON:0001379	97.70	gold quality
urethra	UBERON:0000057	97.66	gold quality
jejunum	UBERON:0002115	97.52	gold quality
left lobe of thyroid gland	UBERON:0001120	97.47	gold quality
deltoid	UBERON:0001476	97.47	gold quality
jejunal mucosa	UBERON:0000399	97.43	gold quality
nephron tubule	UBERON:0001231	97.40	gold quality
thyroid gland	UBERON:0002046	97.34	gold quality
right lobe of thyroid gland	UBERON:0001119	97.33	gold quality
body of tongue	UBERON:0011876	97.27	gold quality
heart right ventricle	UBERON:0002080	97.26	gold quality
middle temporal gyrus	UBERON:0002771	97.23	gold quality
synovial joint	UBERON:0002217	97.22	gold quality
fundus of stomach	UBERON:0001160	97.18	gold quality
quadriceps femoris	UBERON:0001377	97.16	gold quality
left ovary	UBERON:0002119	97.16	gold quality
diaphragm	UBERON:0001103	97.15	gold quality
biceps brachii	UBERON:0001507	97.15	gold quality
cortex of kidney	UBERON:0001225	97.13	gold quality
left ventricle myocardium	UBERON:0006566	97.12	gold quality
tibialis anterior	UBERON:0001385	97.10	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)

37 targeting KLHDC2, 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-LET-7A-3P	100.00	74.03	3932
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-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-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-626	98.89	66.21	762
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-548AT-3P	98.37	64.98	580
HSA-MIR-548AY-3P	98.37	65.14	562
HSA-MIR-15A-3P	97.47	65.08	527

Literature-anchored findings (GeneRIF, showing 2)

• Data show that KLHDC1 and KLHDC2 have differential localization and activity in cultured mammalian cells. (PMID:16964437)
• Three crystal structures have been reported of a CRL2 substrate receptor, KLHDC2, in complex with the diglycine-ending C-end degrons of an early terminated selenoprotein, SelK, and the N-terminal proteolytic fragment of USP1. (PMID:30526872)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhdc2	ENSDARG00000104864
mus_musculus	Klhdc2	ENSMUSG00000020978
rattus_norvegicus	Klhdc2	ENSRNOG00000004474

Paralogs (10): FBXO42 (ENSG00000037637), LZTR1 (ENSG00000099949), KLHDC4 (ENSG00000104731), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), KLHDC10 (ENSG00000128607), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), HCFC1 (ENSG00000172534), KLHDC1 (ENSG00000197776)

Protein

Protein identifiers

Kelch domain-containing protein 2 — Q9Y2U9 (reviewed: Q9Y2U9)

Alternative names: Hepatocellular carcinoma-associated antigen 33, Host cell factor homolog LCP, Host cell factor-like protein 1

All UniProt accessions (3): G3V2H2, G3V3U8, Q9Y2U9

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(KLHDC2) complex specifically recognizes proteins with a diglycine (Gly-Gly) at the C-terminus, leading to their ubiquitination and degradation. The CRL2(KLHDC2) complex mediates ubiquitination and degradation of truncated SELENOK and SELENOS selenoproteins produced by failed UGA/Sec decoding, which end with a diglycine. The CRL2(KLHDC2) complex also recognizes proteolytically cleaved proteins ending with Gly-Gly, such as the N-terminal fragment of USP1, leading to their degradation. May also act as an indirect repressor of CREB3-mediated transcription by interfering with CREB3-DNA-binding.

Subunit / interactions. Component of a CRL2(KLHDC2) E3 ubiquitin-protein ligase complex, also named ECS(KLHDC2) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC2. May form oligomers as a KLHDC2-ELOB-ELOC complex; this interaction is autoinhibitory for the E3 ligase complex as the substrate-binding site of KLHDC2 is blocked in the oligomer. Interacts with CREB3; interaction is direct and specific as it does not interact with CREB1, ATF4, ATF6, JUN, FOS, CEBPA or herpes simplex virus transactivator VP16.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed, with high levels in skeletal muscle, heart, pancreas and liver. Undetectable in peripheral blood leukocytes.

Post-translational modifications. Autoubiquitinated by the CRL2(KLHDC2) E3 ligase complex.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2U9-1	1	yes
Q9Y2U9-2	2

RefSeq proteins (1): NP_055130* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily

Pfam: PF24681

UniProt features (76 total): strand 37, mutagenesis site 17, turn 7, repeat 6, helix 5, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
8EBL	X-RAY DIFFRACTION	1.37
8SGF	X-RAY DIFFRACTION	1.42
8SGE	X-RAY DIFFRACTION	1.51
8EBM	X-RAY DIFFRACTION	1.58
9BCA	X-RAY DIFFRACTION	1.7
9BCC	X-RAY DIFFRACTION	1.7
8PIF	X-RAY DIFFRACTION	1.78
9BC9	X-RAY DIFFRACTION	1.91
8UXS	X-RAY DIFFRACTION	2
6DO3	X-RAY DIFFRACTION	2.17
6DO4	X-RAY DIFFRACTION	2.2
6DO5	X-RAY DIFFRACTION	2.5
8EBN	X-RAY DIFFRACTION	2.6
8SH2	ELECTRON MICROSCOPY	3.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2U9-F1	90.00	0.76

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 (17):

Position	Phenotype
177	impairs oligomerization of klhdc2-elob-eloc complex; when associated with a-182 and a-183. impairs oligomerization of kl
182	impairs oligomerization of klhdc2-elob-eloc complex; when associated with a-177 and a-183.
183	impairs oligomerization of klhdc2-elob-eloc complex; when associated with a-177 and a-182. impairs oligomerization of kl
189	does not affect ability to recognize truncated selenok or cleaved usp1 with a diglycine (gly-gly) at the c-terminus.
236	does not affect ability to recognize truncated selenok with a diglycine (gly-gly) at the c-terminus. abolished ability t
236	abolished ability to recognize truncated selenok with a diglycine (gly-gly) at the c-terminus.
241	abolished ability to recognize truncated selenok or cleaved usp1 with a diglycine (gly-gly) at the c-terminus.
241	does not affect ability to recognize truncated selenok with a diglycine (gly-gly) at the c-terminus. abolished ability t
269	does not affect ability to recognize truncated selenok with a diglycine (gly-gly) at the c-terminus.
269	abolished ability to recognize truncated selenok with a diglycine (gly-gly) at the c-terminus.
269	abolishes oligomerization of klhdc2-elob-eloc complex.
373	impairs oligomerization of klhdc2-elob-eloc complex.
401–406	abolishes oligomerization of klhdc2-elob-eloc complex.
405–406	abolishes oligomerization of klhdc2-elob-eloc complex.
406	promotes oligomerization of klhdc2-elob-eloc complex. abolishes the activity of crl2(klhdc2) complex to ubiquitinate sel
147	strongly impaired ability to recognize truncated selenok or cleaved usp1 with a diglycine (gly-gly) at the c-terminus.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 192 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, FOXO1_01, CAGCTG_AP4_Q5, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GREENBAUM_E2A_TARGETS_UP, LIU_CMYB_TARGETS_UP, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, LIU_VMYB_TARGETS_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_DN, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_NUCLEAR_ENVELOPE, GOCC_TRANSFERASE_COMPLEX, GOCC_NUCLEAR_BODY

GO Biological Process (3): protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627)

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

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), Cul2-RING ubiquitin ligase complex (GO:0031462), nuclear membrane (GO:0031965), cullin-RING ubiquitin ligase complex (GO:0031461)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
cullin-RING ubiquitin ligase complex	1
nucleus	1
nuclear envelope	1
organelle membrane	1
ubiquitin ligase complex	1

Protein interactions and networks

STRING

1290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHDC2	CREB3	O43889	899
KLHDC2	SELENOK	Q9Y6D0	593
KLHDC2	SELENOS	Q9BQE4	589
KLHDC2	KLHL40	Q2TBA0	532
KLHDC2	ELOB	Q15370	523
KLHDC2	CUL2	Q13617	516
KLHDC2	KLHL20	Q9Y2M5	493
KLHDC2	KBTBD13	C9JR72	490
KLHDC2	APPBP2	Q92624	488
KLHDC2	SELENOV	P59797	467
KLHDC2	SEPHS2	Q99611	454
KLHDC2	KLHL41	O60662	445
KLHDC2	KLHL6	Q8WZ60	433
KLHDC2	FEM1C	Q96JP0	430
KLHDC2	PRAMEF6	Q5VXH4	412

IntAct

78 interactions, top by confidence:

A	B	Type	Score
CCM2	KRIT1	psi-mi:“MI:0914”(association)	0.960
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
KLHDC2	NUDCD3	psi-mi:“MI:0915”(physical association)	0.740
KLHDC2	CUL2	psi-mi:“MI:0914”(association)	0.730
CUL2	COPS2	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
GLMN	CUL2	psi-mi:“MI:0914”(association)	0.640
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
DNAAF8	CCDC85C	psi-mi:“MI:0914”(association)	0.530
KLHDC2	PFDN1	psi-mi:“MI:0914”(association)	0.530
GLMN	CUL1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TCEAL1	CHEK1	psi-mi:“MI:0914”(association)	0.530
GCNT3	BCKDK	psi-mi:“MI:0914”(association)	0.530
GLMN	MGST3	psi-mi:“MI:0914”(association)	0.530
NEFM	VWA8	psi-mi:“MI:0914”(association)	0.530
RNF7	SOCS7	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
MTFR2	KLHDC2	psi-mi:“MI:0915”(physical association)	0.400
SFN	KLHDC2	psi-mi:“MI:0915”(physical association)	0.400
Sacm1l	COPE	psi-mi:“MI:0914”(association)	0.350
RNASEH2B	SAP18	psi-mi:“MI:0914”(association)	0.350
ATL2	ACRBP	psi-mi:“MI:0914”(association)	0.350
CHST15	SLC43A3	psi-mi:“MI:0914”(association)	0.350

BioGRID (140): KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), KLHDC2 (Affinity Capture-MS), VIMP (Affinity Capture-MS), RNF169 (Affinity Capture-MS)

ESM2 similar proteins: A2AAX3, A2AUC9, A6QQY2, D3ZA50, G3X9X1, O14682, O15519, O35709, O60662, O94955, Q1LYM6, Q2T9Z7, Q2TBA0, Q2TBA3, Q2WGJ6, Q53GT1, Q568M3, Q56A24, Q5BK60, Q5E9A7, Q5EB39, Q5RD56, Q5RDY3, Q5RGB8, Q5U504, Q5ZJU2, Q5ZLD3, Q60584, Q6DEL7, Q6INL2, Q6TFL4, Q6V595, Q6ZPT1, Q7ZX59, Q80TF4, Q80YG3, Q8BRG6, Q8BSF5, Q8IY47, Q8N7A1

Diamond homologs: Q3KRE6, Q4G5Y1, Q5E9A7, Q5ZJ37, Q80YG3, Q8N7A1, Q9Y2U9, Q2QM47, Q4V8F4, Q60EX6, Q86L99, Q8L7U5, Q8W4K1, Q9SHS7, Q9SJF0, A1XLE2, G1FNI6, O04318, Q5EA50, Q7Z6M1, Q8VCH5, Q9SDM9, A5F7B3, A8JAM0, Q39610, Q9KR69

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	74.6×	8e-10
Activation of BAD and translocation to mitochondria	6	72.5×	1e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	64.0×	2e-08
Activation of BH3-only proteins	6	47.3×	1e-07
RHO GTPases activate PKNs	6	30.2×	2e-06
Intrinsic Pathway for Apoptosis	6	27.9×	3e-06
FOXO-mediated transcription	5	26.7×	4e-05
SARS-CoV-1-host interactions	6	16.7×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	10	6.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	53
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
4685090	NM_004713.6(NEMF):c.3045_3048del (p.Thr1016fs)	Pathogenic
2432191	NM_004713.6(NEMF):c.2943_2950del (p.Ser982fs)	Likely pathogenic

SpliceAI

1783 predictions. Top by Δscore:

Variant	Effect	Δscore
14:49768622:GTCA:G	donor_gain	1.0000
14:49768626:G:GG	donor_gain	1.0000
14:49771592:A:AG	acceptor_gain	1.0000
14:49771593:G:GG	acceptor_gain	1.0000
14:49771593:GA:G	acceptor_gain	1.0000
14:49771593:GAGT:G	acceptor_gain	1.0000
14:49771593:GAGTA:G	acceptor_gain	1.0000
14:49771670:GATG:G	donor_gain	1.0000
14:49774559:A:AG	acceptor_gain	1.0000
14:49774559:AG:A	acceptor_gain	1.0000
14:49774560:G:A	acceptor_loss	1.0000
14:49774560:G:GA	acceptor_gain	1.0000
14:49774560:GG:G	acceptor_gain	1.0000
14:49774560:GGA:G	acceptor_gain	1.0000
14:49774560:GGAA:G	acceptor_gain	1.0000
14:49774560:GGAAA:G	acceptor_gain	1.0000
14:49774674:ATAAG:A	donor_loss	1.0000
14:49774678:GGT:G	donor_loss	1.0000
14:49777837:A:AG	acceptor_gain	1.0000
14:49777838:G:GA	acceptor_gain	1.0000
14:49777950:AACAA:A	donor_gain	1.0000
14:49777951:ACAA:A	donor_gain	1.0000
14:49777952:CAA:C	donor_gain	1.0000
14:49777955:G:GG	donor_gain	1.0000
14:49778172:CAACA:C	acceptor_loss	1.0000
14:49778174:ACAG:A	acceptor_loss	1.0000
14:49778175:CAGGT:C	acceptor_loss	1.0000
14:49778176:A:AG	acceptor_gain	1.0000
14:49778176:A:T	acceptor_loss	1.0000
14:49778177:G:GC	acceptor_loss	1.0000

AlphaMissense

2678 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:49768562:C:A	R32S	1.000
14:49768568:G:C	G34R	1.000
14:49768569:G:A	G34D	1.000
14:49768569:G:T	G34V	1.000
14:49768577:G:C	A37P	1.000
14:49768578:C:A	A37D	1.000
14:49768605:T:A	V46D	1.000
14:49768610:G:C	G48R	1.000
14:49768611:G:A	G48D	1.000
14:49768611:G:T	G48V	1.000
14:49768614:G:A	G49D	1.000
14:49771645:T:A	W69R	1.000
14:49771645:T:C	W69R	1.000
14:49771672:T:A	W78R	1.000
14:49771672:T:C	W78R	1.000
14:49774605:G:A	G93E	1.000
14:49774647:G:A	G107E	1.000
14:49774650:G:A	G108E	1.000
14:49777881:T:A	W132R	1.000
14:49777881:T:C	W132R	1.000
14:49777923:G:C	D146H	1.000
14:49777924:A:C	D146A	1.000
14:49777924:A:G	D146G	1.000
14:49777924:A:T	D146V	1.000
14:49777926:A:G	K147E	1.000
14:49777927:A:T	K147I	1.000
14:49777928:A:C	K147N	1.000
14:49777928:A:T	K147N	1.000
14:49777938:T:A	W151R	1.000
14:49777938:T:C	W151R	1.000

dbSNP variants (sampled 300 via entrez): RS1000063197 (14:49779175 G>A), RS1000163624 (14:49773346 A>G), RS1000322368 (14:49768065 C>A,T), RS1000419891 (14:49785161 C>A,G,T), RS1000531566 (14:49772790 C>T), RS1000709489 (14:49773738 G>C), RS1000815730 (14:49767390 C>T), RS1001161556 (14:49783568 G>T), RS1001359877 (14:49784127 A>G), RS1001540858 (14:49769657 C>T), RS1001548919 (14:49768211 T>G), RS1001815994 (14:49768191 C>T), RS1001824690 (14:49786590 G>A,C), RS1001862579 (14:49772985 CTAAAAA>C), RS1001996529 (14:49768479 G>A)

Disease associations

OMIM: gene MIM:611280 | disease phenotypes: MIM:619099

GenCC curated gene-disease

Mondo (1): intellectual developmental disorder with speech delay and axonal peripheral neuropathy (MONDO:0030849)

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): CHEMBL6066380 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — E3 ubiquitin ligase components

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
KYH1872	Binding	8.7	pKd

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
6.44	Kd	360	nM	CHEMBL5566038

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-[5-[3-[(2R)-butan-2-yl]-7-(2-methoxyethoxycarbonyl)-2-oxo-6,8-dihydro-5H-1,7-naphthyridin-1-yl]-2-oxo-1-pyridinyl]acetic acid	2107802: Binding affinity to KLHDC2 (unknown origin)	kd	0.3600	uM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Valproic Acid	decreases expression, affects expression	2
Cyclosporine	increases expression, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
periodate-oxidized adenosine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Pamidronate	decreases expression	1
Acetaminophen	decreases expression	1
Benztropine	affects cotreatment, increases expression	1
Cadmium	increases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Clozapine	decreases expression	1
Cuprizone	affects cotreatment, increases expression, decreases expression	1
Estradiol	decreases 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
CHEMBL5551129	Binding	Binding affinity to KLHDC2 (unknown origin)	Expanding the ligand spaces for E3 ligases for the design of protein degraders. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7GQ	Ubigene HEK293T KLHDC2 KO	Transformed cell line	Female
CVCL_E2AF	HAP1 KLHDC2 (-) 1	Cancer cell line	Male
CVCL_E2AG	HAP1 KLHDC2 (-) 2	Cancer cell line	Male
CVCL_E2AH	HAP1 KLHDC2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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