KLHDC4

Summary

KLHDC4 (kelch domain containing 4, HGNC:25272) is a protein-coding gene on chromosome 16q24.2, encoding Kelch domain-containing protein 4 (Q8TBB5).

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 181 total
• Druggable target: yes
• MANE Select transcript: NM_017566

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25272
Approved symbol	KLHDC4
Name	kelch domain containing 4
Location	16q24.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434G0522
Ensembl gene	ENSG00000104731
Ensembl biotype	protein_coding
OMIM	620518
Entrez	54758

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 26 protein_coding, 9 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay, 4 retained_intron

ENST00000270583, ENST00000316853, ENST00000347925, ENST00000353170, ENST00000446344, ENST00000561825, ENST00000562155, ENST00000562261, ENST00000562872, ENST00000562913, ENST00000563845, ENST00000564396, ENST00000564484, ENST00000565328, ENST00000566349, ENST00000566561, ENST00000566661, ENST00000567298, ENST00000567513, ENST00000568338, ENST00000568346, ENST00000568444, ENST00000568499, ENST00000568502, ENST00000569487, ENST00000569747, ENST00000909874, ENST00000909875, ENST00000909876, ENST00000909877, ENST00000909878, ENST00000909879, ENST00000909880, ENST00000919679, ENST00000919680, ENST00000919681, ENST00000919682, ENST00000919683, ENST00000919684, ENST00000968624, ENST00000968625, ENST00000968626, ENST00000968627, ENST00000968628, ENST00000968629, ENST00000968630

RefSeq mRNA: 5 — MANE Select: NM_017566 NM_001184854, NM_001184856, NM_001351937, NM_001351938, NM_017566

CCDS: CCDS10963, CCDS54050, CCDS54051

Canonical transcript exons

ENST00000270583 — 12 exons

Exon	Start	End
ENSE00001857405	87707812	87708075
ENSE00002320116	87761949	87762040
ENSE00002606020	87765792	87765986
ENSE00003485565	87756399	87756477
ENSE00003525219	87714498	87714573
ENSE00003527428	87730552	87730644
ENSE00003537177	87711235	87711443
ENSE00003565877	87709265	87709667
ENSE00003652524	87726765	87726924
ENSE00003660224	87708350	87708466
ENSE00003669649	87755194	87755292
ENSE00003673570	87748673	87748809

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 96.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.5713 / max 343.7639, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158481	23.5545	1819
158479	0.0168	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.34	gold quality
granulocyte	CL:0000094	95.90	gold quality
left testis	UBERON:0004533	94.70	gold quality
right testis	UBERON:0004534	94.63	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.09	gold quality
cerebellar hemisphere	UBERON:0002245	92.98	gold quality
cerebellar cortex	UBERON:0002129	92.80	gold quality
body of pancreas	UBERON:0001150	92.02	gold quality
cervix squamous epithelium	UBERON:0006922	91.19	silver quality
mucosa of stomach	UBERON:0001199	91.08	gold quality
testis	UBERON:0000473	90.88	gold quality
body of stomach	UBERON:0001161	90.85	gold quality
transverse colon	UBERON:0001157	90.60	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.59	gold quality
right lobe of thyroid gland	UBERON:0001119	90.58	gold quality
left lobe of thyroid gland	UBERON:0001120	90.52	gold quality
apex of heart	UBERON:0002098	90.49	gold quality
left ovary	UBERON:0002119	90.23	gold quality
adenohypophysis	UBERON:0002196	90.22	gold quality
cerebellum	UBERON:0002037	90.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.14	gold quality
spleen	UBERON:0002106	89.92	gold quality
minor salivary gland	UBERON:0001830	89.91	gold quality
right uterine tube	UBERON:0001302	89.87	gold quality
body of uterus	UBERON:0009853	89.84	gold quality
right lobe of liver	UBERON:0001114	89.78	gold quality
metanephros cortex	UBERON:0010533	89.75	gold quality
right frontal lobe	UBERON:0002810	89.61	gold quality
anterior cingulate cortex	UBERON:0009835	89.51	gold quality
skin of leg	UBERON:0001511	89.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting KLHDC4, 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-1297	99.91	73.41	3162
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-4486	96.96	60.61	931

Literature-anchored findings (GeneRIF, showing 1)

• KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. (PMID:27030985)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhdc4	ENSDARG00000100206
mus_musculus	Klhdc4	ENSMUSG00000040263
rattus_norvegicus	Klhdc4	ENSRNOG00000018801
drosophila_melanogaster	CG4069	FBGN0036301
drosophila_melanogaster	slim	FBGN0261477

Paralogs (10): FBXO42 (ENSG00000037637), LZTR1 (ENSG00000099949), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), KLHDC10 (ENSG00000128607), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), KLHDC2 (ENSG00000165516), HCFC1 (ENSG00000172534), KLHDC1 (ENSG00000197776)

Protein

Protein identifiers

Kelch domain-containing protein 4 — Q8TBB5 (reviewed: Q8TBB5)

All UniProt accessions (9): Q8TBB5, H3BP99, H3BQ90, H3BQH3, H3BQL0, H3BTB1, H3BUX8, H3BV82, Q86VH3

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TBB5-1	1	yes
Q8TBB5-2	2
Q8TBB5-3	3

RefSeq proteins (5): NP_001171783, NP_001171785, NP_001338866, NP_001338867, NP_060036* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR052588	Kelch_domain_protein	Family

Pfam: PF24681

UniProt features (21 total): repeat 6, region of interest 4, sequence variant 4, compositionally biased region 2, modified residue 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TBB5-F1	81.43	0.63

Functional residue map

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

Post-translational modifications (2): 413, 418

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 79 (showing top): NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, BROWN_MYELOID_CELL_DEVELOPMENT_UP, FISCHER_DREAM_TARGETS, MGGAAGTG_GABP_B, TOYOTA_TARGETS_OF_MIR34B_AND_MIR34C, MARTENS_BOUND_BY_PML_RARA_FUSION, CAMP_UP.V1_DN, ATF6_TARGET_GENES, GSE13547_WT_VS_ZFX_KO_BCELL_ANTI_IGM_STIM_2H_UP, DIDO1_TARGET_GENES, ELF2_TARGET_GENES, HES2_TARGET_GENES, HEY2_TARGET_GENES, NFKBIA_TARGET_GENES, SNAI1_TARGET_GENES

GO Biological Process (0):

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

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1

Protein interactions and networks

STRING

1102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHDC4	ARMC6	Q6NXE6	510
KLHDC4	SHCBP1	Q8NEM2	453
KLHDC4	ARMC7	Q9H6L4	447
KLHDC4	ZCCHC14	Q8WYQ9	447
KLHDC4	DMAC1	Q96GE9	432
KLHDC4	GARIN1B	Q96KD3	404
KLHDC4	TRAPPC2L	Q9UL33	399
KLHDC4	MEAK7	Q6P9B6	395
KLHDC4	KLHDC8A	Q8IYD2	388
KLHDC4	SYTL3	Q4VX76	387
KLHDC4	KLHDC8B	Q8IXV7	380
KLHDC4	C16orf95	Q9H693	380
KLHDC4	ZNF185	O15231	375
KLHDC4	TMEM41B	Q5BJD5	375
KLHDC4	RBMS2	Q15434	373

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CEP76	KLHDC4	psi-mi:“MI:0915”(physical association)	0.560
TERF1	KLHDC4	psi-mi:“MI:0915”(physical association)	0.510
SUV39H2	KLHDC4	psi-mi:“MI:0915”(physical association)	0.510
KLHDC4	SUV39H1	psi-mi:“MI:0915”(physical association)	0.510
KLHDC4	KDM1A	psi-mi:“MI:0915”(physical association)	0.510
KDM1A	KLHDC4	psi-mi:“MI:0915”(physical association)	0.510
SUV39H1	KLHDC4	psi-mi:“MI:0915”(physical association)	0.510
KLHDC4	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
KLHDC4	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
KLHDC4	NCL	psi-mi:“MI:0915”(physical association)	0.400
N	RBM47	psi-mi:“MI:0914”(association)	0.350
CROT	KLHDC4	psi-mi:“MI:0914”(association)	0.350
AHR	SHTN1	psi-mi:“MI:0914”(association)	0.350
CES2	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
KLHDC4	TERF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (43): CEP76 (Two-hybrid), KLHDC4 (Affinity Capture-RNA), KLHDC4 (Affinity Capture-RNA), KLHDC4 (Affinity Capture-RNA), KLHDC4 (Affinity Capture-MS), RPS19 (Co-fractionation), KLHDC4 (Affinity Capture-MS), KLHDC4 (Reconstituted Complex), KLHDC4 (Affinity Capture-MS), KLHDC4 (Affinity Capture-MS), KLHDC4 (Proximity Label-MS), KLHDC4 (Proximity Label-MS), KLHDC4 (Affinity Capture-MS), KLHDC4 (Two-hybrid), KLHDC4 (Two-hybrid)

ESM2 similar proteins: A0A8I5ZNK2, A2AWP8, A4IIX9, A5D7H2, A6QLH6, D4ABL6, E9PV86, F1QH17, O14908, O88506, O95747, P58405, Q13033, Q29RM4, Q3SYZ2, Q52KW8, Q5NVK4, Q5R495, Q5R5M3, Q5R650, Q5R8W1, Q5XIS9, Q6DDF0, Q6NYE2, Q6P9R2, Q6QEF8, Q863I2, Q8BH44, Q8BK67, Q8BZ03, Q8CBE3, Q8TBB5, Q8TF64, Q91XI1, Q920J3, Q920M5, Q921I2, Q96G46, Q9BR76, Q9BZL6

Diamond homologs: Q28DE7, Q5R8W1, Q5U580, Q86L99, Q8TBB5, Q921I2, Q9C9W9, A2AB59, A8JAM0, B0S6J3, B2RTY4, E7EZG2, E7F3F0, O14248, O43295, O75044, P38853, P46941, P50090, P80197, P81128, P83509, P85298, P87061, P98171, Q07960, Q0IIC2, Q10164, Q10AZ7, Q12128, Q2QM47, Q39610, Q4V8F4, Q54E35, Q54F80, Q54FG5, Q54SL6, Q54TH9, Q54WY8, Q54YV1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	145
Likely benign	14
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3463 predictions. Top by Δscore:

Variant	Effect	Δscore
16:87708467:C:CC	acceptor_gain	1.0000
16:87708470:C:CT	acceptor_gain	1.0000
16:87708476:C:CT	acceptor_gain	1.0000
16:87708477:A:T	acceptor_gain	1.0000
16:87711229:CACTA:C	donor_loss	1.0000
16:87711230:ACTAC:A	donor_loss	1.0000
16:87711231:CTACC:C	donor_loss	1.0000
16:87711232:TAC:T	donor_loss	1.0000
16:87711233:A:C	donor_loss	1.0000
16:87711261:T:A	donor_gain	1.0000
16:87711439:CTTGT:C	acceptor_gain	1.0000
16:87711440:TTGT:T	acceptor_gain	1.0000
16:87711441:TGT:T	acceptor_gain	1.0000
16:87711442:GT:G	acceptor_gain	1.0000
16:87711443:TC:T	acceptor_loss	1.0000
16:87711444:C:CC	acceptor_gain	1.0000
16:87711445:T:A	acceptor_loss	1.0000
16:87711448:C:CT	acceptor_gain	1.0000
16:87711449:A:T	acceptor_gain	1.0000
16:87714570:CTCT:C	acceptor_gain	1.0000
16:87714572:CT:C	acceptor_gain	1.0000
16:87729375:A:T	acceptor_gain	1.0000
16:87730561:T:A	donor_gain	1.0000
16:87730640:TTGAT:T	acceptor_gain	1.0000
16:87730642:GAT:G	acceptor_gain	1.0000
16:87730645:C:CA	acceptor_loss	1.0000
16:87730645:C:CC	acceptor_gain	1.0000
16:87730650:A:AC	acceptor_gain	1.0000
16:87748671:A:AC	donor_gain	1.0000
16:87748672:C:CC	donor_gain	1.0000

AlphaMissense

3402 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:87730566:G:C	F195L	0.999
16:87730566:G:T	F195L	0.999
16:87730568:A:G	F195L	0.999
16:87748686:A:G	W165R	0.999
16:87748686:A:T	W165R	0.999
16:87755244:A:G	W107R	0.999
16:87755244:A:T	W107R	0.999
16:87711255:A:G	W342R	0.998
16:87711255:A:T	W342R	0.998
16:87711432:A:G	W283R	0.998
16:87711432:A:T	W283R	0.998
16:87726872:A:G	W218R	0.998
16:87726872:A:T	W218R	0.998
16:87748732:G:C	F149L	0.998
16:87748732:G:T	F149L	0.998
16:87748734:A:G	F149L	0.998
16:87748776:A:G	W135R	0.998
16:87748776:A:T	W135R	0.998
16:87709370:C:A	G448W	0.997
16:87711341:C:T	G313E	0.997
16:87730570:C:T	G194D	0.997
16:87730573:C:T	G193D	0.997
16:87730617:A:C	S178R	0.997
16:87730617:A:T	S178R	0.997
16:87730619:T:G	S178R	0.997
16:87709369:C:T	G448E	0.996
16:87726778:C:T	G249D	0.996
16:87726781:C:T	G248E	0.996
16:87730609:C:G	R181P	0.996
16:87748684:C:A	W165C	0.996

dbSNP variants (sampled 300 via entrez): RS1000046087 (16:87721009 C>T), RS1000046866 (16:87743394 C>A,T), RS1000071636 (16:87716101 G>A,T), RS1000090459 (16:87705377 T>C), RS1000095938 (16:87727096 G>A,C), RS1000096136 (16:87758413 T>A), RS1000104680 (16:87724020 T>C,G), RS1000121513 (16:87705522 A>G), RS1000132442 (16:87715426 G>T), RS1000156403 (16:87746418 A>C), RS1000216379 (16:87759792 C>G), RS1000218582 (16:87736557 T>C), RS1000244511 (16:87749737 T>A), RS1000268877 (16:87759683 T>C), RS1000281626 (16:87707001 A>G)

Disease associations

OMIM: gene MIM:620518 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007013_4	Hippocampal volume in mild cognitive impairment	8.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196114 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
bisphenol S	decreases methylation, affects cotreatment, decreases expression	2
Acrolein	increases abundance, affects cotreatment, increases oxidation	2
Ozone	increases oxidation, increases abundance, affects cotreatment	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects methylation, affects cotreatment, decreases methylation	1
butyraldehyde	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	increases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Testosterone	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
CHEMBL6094275	Binding	Binding affinity to KLHDC4 (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)

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