KLHL26

Summary

KLHL26 (kelch like family member 26, HGNC:25623) is a protein-coding gene on chromosome 19p13.11, encoding Kelch-like protein 26 (Q53HC5). May play a role in endo(sarco)plasmic reticulum (ER/SR) mitochondrial signaling.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 108 total
• Druggable target: yes
• MANE Select transcript: NM_018316

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25623
Approved symbol	KLHL26
Name	kelch like family member 26
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167487
Ensembl biotype	protein_coding
Entrez	55295

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000300976, ENST00000595182, ENST00000595423, ENST00000596843, ENST00000599006, ENST00000600657

RefSeq mRNA: 6 — MANE Select: NM_018316 NM_001345981, NM_001345982, NM_001345983, NM_001345984, NM_001345985, NM_018316

CCDS: CCDS12384, CCDS86726, CCDS86727

Canonical transcript exons

ENST00000300976 — 3 exons

Exon	Start	End
ENSE00001123057	18667664	18671721
ENSE00001183319	18637028	18637137
ENSE00003555092	18664261	18664443

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 93.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.8922 / max 62.5457, expressed in 1626 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174714	4.2645	1561
174715	0.6277	333

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.99	gold quality
oocyte	CL:0000023	93.81	gold quality
popliteal artery	UBERON:0002250	89.44	gold quality
tibial artery	UBERON:0007610	89.41	gold quality
aorta	UBERON:0000947	85.09	gold quality
prefrontal cortex	UBERON:0000451	83.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.86	gold quality
right frontal lobe	UBERON:0002810	81.79	gold quality
frontal cortex	UBERON:0001870	81.64	gold quality
postcentral gyrus	UBERON:0002581	81.32	gold quality
left coronary artery	UBERON:0001626	81.29	gold quality
cortical plate	UBERON:0005343	80.86	gold quality
neocortex	UBERON:0001950	80.84	gold quality
coronary artery	UBERON:0001621	80.45	gold quality
superior frontal gyrus	UBERON:0002661	80.17	gold quality
entorhinal cortex	UBERON:0002728	80.13	gold quality
nucleus accumbens	UBERON:0001882	80.01	gold quality
caudate nucleus	UBERON:0001873	80.00	gold quality
gastrocnemius	UBERON:0001388	79.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.67	gold quality
anterior cingulate cortex	UBERON:0009835	79.60	gold quality
cingulate cortex	UBERON:0003027	79.56	gold quality
thoracic aorta	UBERON:0001515	79.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.53	gold quality
ascending aorta	UBERON:0001496	79.52	gold quality
cerebral cortex	UBERON:0000956	79.46	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.37	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.14	gold quality
descending thoracic aorta	UBERON:0002345	79.12	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting KLHL26, 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-5196-5P	100.00	67.98	2761
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
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-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-4524A-3P	99.72	66.85	2406

Literature-anchored findings (GeneRIF, showing 1)

• Novel KLHL26 variant associated with a familial case of Ebstein’s anomaly and left ventricular noncompaction. (PMID:31985165)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl26	ENSDARG00000053876
mus_musculus	Klhl26	ENSMUSG00000055707
rattus_norvegicus	Klhl26	ENSRNOG00000020088

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), 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 26 — Q53HC5 (reviewed: Q53HC5)

All UniProt accessions (5): Q53HC5, M0QXE1, M0R049, M0R1N0, M0R1P3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in endo(sarco)plasmic reticulum (ER/SR) mitochondrial signaling. May be part of the ubiquitin-proteasome system (UPS) and affect ubiquitination and degradation of target substrates in cardiomyocytes.

Disease relevance. Defects in KLHL26 may be cause of autosomal dominant inheritance of Ebstein’s anomaly and left ventricular non-compaction.

RefSeq proteins (5): NP_001332910, NP_001332911, NP_001332913, NP_001332914, NP_060786* (*=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
IPR030588	BTB_POZ_KLHL26	Domain

Pfam: PF00651, PF01344, PF07707

UniProt features (30 total): helix 7, strand 6, repeat 6, sequence variant 2, domain 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9ETW	X-RAY DIFFRACTION	1.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53HC5-F1	91.98	0.85

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 (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 75 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX, GOCC_CUL3_RING_UBIQUITIN_LIGASE_COMPLEX, chr19p13, RAY_TUMORIGENESIS_BY_ERBB2_CDC25A_DN, GOCC_UBIQUITIN_LIGASE_COMPLEX, KOYAMA_SEMA3B_TARGETS_DN, LINSLEY_MIR16_TARGETS, NOTCH_DN.V1_UP

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

726 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL26	CIMAP1D	Q3SX64	591
KLHL26	OR2A12	Q8NGT7	574
KLHL26	ERICH3	Q5RHP9	543
KLHL26	CIB3	Q96Q77	516
KLHL26	PLCD4	Q9BRC7	488
KLHL26	SAXO2	Q658L1	466
KLHL26	NEB	P20929	445
KLHL26	QPCT	Q16769	415
KLHL26	SPDYC	Q5MJ68	404
KLHL26	DNAJC5B	Q9UF47	403
KLHL26	NEDD8	Q15843	391
KLHL26	NUP210L	Q5VU65	387
KLHL26	MCMDC2	Q4G0Z9	379
KLHL26	CCDC63	Q8NA47	361
KLHL26	ATP8A1	Q9Y2Q0	357

IntAct

145 interactions, top by confidence:

A	B	Type	Score
KLHL9	CUL3	psi-mi:“MI:0914”(association)	0.860
KLHL12	KLHL2	psi-mi:“MI:0914”(association)	0.850
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
KLHL26	CUL3	psi-mi:“MI:0914”(association)	0.730
KLHL24	CUL3	psi-mi:“MI:0914”(association)	0.730
FBXL17	BACH1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
KLHL13	COPS2	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
KLHL21	CUL3	psi-mi:“MI:0914”(association)	0.640
KLHL25	ENC1	psi-mi:“MI:0914”(association)	0.640
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
ANKS1A	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
AQP1	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
KLHL26	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
KLHL26	NUDT22	psi-mi:“MI:0915”(physical association)	0.560
ZIC1	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
PITX1	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
PRR35	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
OTX1	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
KLHL26	KCTD9	psi-mi:“MI:0915”(physical association)	0.560
POGZ	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
INCA1	KLHL26	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	KLHL26	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (127): KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Q1W5, B0WWP2, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, E9Q4F2, O14682, O35709, O94889, P28575, P59280, Q08BL9, Q08DK3, Q0D2A9, Q16RL8, Q1ECZ2, Q1LYM6, Q2M0J9, Q4KLM4, Q53HC5, Q56A24, Q5R7B8, Q5RGB8, Q5ZKD9, Q6DFF6, Q6DFF7, Q6TDP3, Q6TDP4, Q6TFL4, Q6V595, Q7QGL0, Q8BRG6

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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	17	10.1×	3e-10
Class I MHC mediated antigen processing & presentation	10	8.8×	4e-05
Antigen processing: Ubiquitination & Proteasome degradation	11	5.1×	1e-03
Adaptive Immune System	11	4.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	5	14.8×	3e-03
protein ubiquitination	20	7.1×	4e-09
protein folding	8	7.1×	3e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	15	6.8×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	98
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

680 predictions. Top by Δscore:

Variant	Effect	Δscore
19:18637134:ACAGG:A	donor_loss	1.0000
19:18637135:CAGGT:C	donor_loss	1.0000
19:18637136:AGGTG:A	donor_loss	1.0000
19:18637137:GGTGA:G	donor_loss	1.0000
19:18637138:GTGA:G	donor_loss	1.0000
19:18637139:T:G	donor_loss	1.0000
19:18664259:A:AG	acceptor_gain	1.0000
19:18664259:AGCAC:A	acceptor_gain	1.0000
19:18664260:G:GG	acceptor_gain	1.0000
19:18664260:GCAC:G	acceptor_gain	1.0000
19:18664260:GCACG:G	acceptor_gain	1.0000
19:18664440:TCAGG:T	donor_loss	1.0000
19:18664441:CAG:C	donor_gain	1.0000
19:18664441:CAGGT:C	donor_loss	1.0000
19:18664442:AG:A	donor_gain	1.0000
19:18664442:AGGT:A	donor_loss	1.0000
19:18664443:GG:G	donor_gain	1.0000
19:18664443:GGT:G	donor_loss	1.0000
19:18664444:G:GG	donor_gain	1.0000
19:18659668:T:A	acceptor_gain	0.9900
19:18659669:G:A	acceptor_gain	0.9900
19:18664257:GCA:G	acceptor_loss	0.9900
19:18664258:CA:C	acceptor_loss	0.9900
19:18664260:GC:G	acceptor_gain	0.9900
19:18664260:GCA:G	acceptor_gain	0.9900
19:18664439:TTCAG:T	donor_gain	0.9900
19:18664440:TCAG:T	donor_gain	0.9900
19:18667658:CTTCA:C	acceptor_loss	0.9900
19:18667659:TTCA:T	acceptor_loss	0.9900
19:18667660:TCA:T	acceptor_loss	0.9900

AlphaMissense

4004 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:18669159:T:A	W588R	1.000
19:18669159:T:C	W588R	1.000
19:18669161:G:C	W588C	1.000
19:18669161:G:T	W588C	1.000
19:18664430:A:C	S85R	0.999
19:18664432:C:A	S85R	0.999
19:18664432:C:G	S85R	0.999
19:18668604:C:A	R403S	0.999
19:18668613:T:C	F406L	0.999
19:18668615:C:A	F406L	0.999
19:18668615:C:G	F406L	0.999
19:18668715:T:A	W440R	0.999
19:18668715:T:C	W440R	0.999
19:18668717:G:C	W440C	0.999
19:18668717:G:T	W440C	0.999
19:18668859:T:A	W488R	0.999
19:18668859:T:C	W488R	0.999
19:18668861:G:C	W488C	0.999
19:18668861:G:T	W488C	0.999
19:18668938:G:A	G514E	0.999
19:18668941:G:A	G515D	0.999
19:18669012:T:A	W539R	0.999
19:18669012:T:C	W539R	0.999
19:18669014:G:C	W539C	0.999
19:18669014:G:T	W539C	0.999
19:18669091:G:A	G565E	0.999
19:18669138:T:G	Y581D	0.999
19:18664422:C:A	A82D	0.998
19:18667755:T:C	F120L	0.998
19:18667757:C:A	F120L	0.998

dbSNP variants (sampled 300 via entrez): RS1000018416 (19:18639933 G>A,C), RS1000052547 (19:18656620 G>A,T), RS1000100033 (19:18662260 C>G,T), RS1000143534 (19:18642996 A>G), RS1000220741 (19:18658300 G>A,T), RS1000257590 (19:18662023 G>A), RS1000285108 (19:18639275 A>G), RS1000566319 (19:18644840 C>T), RS1000585111 (19:18639602 G>T), RS1000587829 (19:18650516 T>C), RS1000619013 (19:18650661 G>A), RS1000698529 (19:18666040 G>A), RS1000797040 (19:18670931 T>C,G), RS1000828180 (19:18670672 G>A,T), RS1000936893 (19:18644645 T>G)

Disease associations

OMIM: gene `` | 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
GCST008832_21	Gastroesophageal reflux disease	2.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196098 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, increases expression	2
aristolochic acid I	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	increases expression	1
Atrazine	increases expression	1
Doxorubicin	increases expression	1
Methapyrilene	increases methylation	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Acrylamide	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
CHEMBL6096342	Binding	Binding affinity to human KLHL26 BTB domain (34 to 161 residues) extracted from Escherichia coli BL21(DE3)-R3-pRARE2 cells assessed as adduct formation at 100 uM by LC-MS analysis	Covalent Inhibitors of KEAP1 with Exquisite Selectivity. — J Med Chem

Clinical trials (associated diseases)

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