KLHL35

Summary

KLHL35 (kelch like family member 35, HGNC:26597) is a protein-coding gene on chromosome 11q13.4, encoding Kelch-like protein 35 (Q6PF15).

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm.

Source: NCBI Gene 283212 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 157 total
• MANE Select transcript: NM_001039548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26597
Approved symbol	KLHL35
Name	kelch like family member 35
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33790
Ensembl gene	ENSG00000149243
Ensembl biotype	protein_coding
Entrez	283212

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 retained_intron, 1 TEC

ENST00000376292, ENST00000460787, ENST00000527491, ENST00000539798, ENST00000624466, ENST00000905843

RefSeq mRNA: 1 — MANE Select: NM_001039548 NM_001039548

CCDS: CCDS44685

Canonical transcript exons

ENST00000539798 — 7 exons

Exon	Start	End
ENSE00001470094	75425393	75425581
ENSE00001470097	75426520	75426638
ENSE00001470099	75428442	75428626
ENSE00001791866	75422394	75422768
ENSE00002274616	75429749	75430630
ENSE00003546966	75423692	75423880
ENSE00003908671	75433043	75433203

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 87.31.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5596 / max 38.3206, expressed in 662 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121356	1.1794	589
121352	0.1180	43
121357	0.0923	35
121355	0.0860	32
121354	0.0561	22
121353	0.0278	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	87.31	gold quality
frontal pole	UBERON:0002795	87.17	gold quality
middle frontal gyrus	UBERON:0002702	84.48	gold quality
endometrium epithelium	UBERON:0004811	83.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.30	gold quality
cortical plate	UBERON:0005343	82.14	gold quality
paraflocculus	UBERON:0005351	81.83	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.68	gold quality
nucleus accumbens	UBERON:0001882	79.43	gold quality
metanephric glomerulus	UBERON:0004736	79.03	gold quality
prefrontal cortex	UBERON:0000451	77.42	gold quality
Brodmann (1909) area 10	UBERON:0013541	77.24	gold quality
right testis	UBERON:0004534	76.85	gold quality
left testis	UBERON:0004533	76.69	gold quality
putamen	UBERON:0001874	76.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	76.20	gold quality
caudate nucleus	UBERON:0001873	75.57	gold quality
testis	UBERON:0000473	75.52	gold quality
colonic epithelium	UBERON:0000397	75.46	gold quality
right frontal lobe	UBERON:0002810	74.50	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	74.30	gold quality
secondary oocyte	CL:0000655	74.24	gold quality
hypothalamus	UBERON:0001898	73.98	gold quality
anterior cingulate cortex	UBERON:0009835	73.95	gold quality
frontal cortex	UBERON:0001870	73.74	gold quality
neocortex	UBERON:0001950	73.59	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.54	gold quality
spinal cord	UBERON:0002240	72.55	gold quality
cerebellar vermis	UBERON:0004720	72.24	gold quality
cerebral cortex	UBERON:0000956	71.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.63

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klhl35	ENSMUSG00000035298
rattus_norvegicus	Klhl35	ENSRNOG00000017365

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), 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 35 — Q6PF15 (reviewed: Q6PF15)

All UniProt accessions (2): Q6PF15, A0A0C4DFW7

UniProt curated annotations — full annotation on UniProt →

Isoforms (2)

UniProt ID	Names	Canonical?
Q6PF15-1	1	yes
Q6PF15-2	2

RefSeq proteins (1): NP_001034637* (*=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
IPR030601	KLHL35_BTB_POZ_dom	Domain

Pfam: PF00651, PF01344, PF07707, PF24681

UniProt features (12 total): repeat 6, splice variant 3, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PF15-F1	89.63	0.74

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): BENPORATH_ES_WITH_H3K27ME3, CMYB_01, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, TAL1ALPHAE47_01, CACCAGC_MIR138, chr11q13, TGTGTGA_MIR377, HIF1_Q3, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, E2F_Q6_01, GOBP_PROTEIN_CATABOLIC_PROCESS, TAL1BETAE47_01, YAGI_AML_WITH_11Q23_REARRANGED

GO Biological Process (1): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

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

GO Cellular Component (2): cytoplasm (GO:0005737), Cul3-RING ubiquitin ligase complex (GO:0031463)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL35	ANKS1A	Q92625	511
KLHL35	TCP11	Q8WWU5	510
KLHL35	ZSCAN18	Q8TBC5	507
KLHL35	CORO6	Q6QEF8	505
KLHL35	GCC2	Q8IWJ2	496
KLHL35	PI15	O43692	491
KLHL35	FAM180A	Q6UWF9	486
KLHL35	CCDC8	Q9H0W5	483
KLHL35	SCUBE3	Q8IX30	479
KLHL35	DLEU7	Q6UYE1	470
KLHL35	ATP5MC2	Q06055	450
KLHL35	FANCE	Q9HB96	444
KLHL35	DEGS2	Q6QHC5	432
KLHL35	CEND1	Q8N111	393
KLHL35	QPCT	Q16769	389

IntAct

27 interactions, top by confidence:

A	B	Type	Score
APPBP2	KLHL35	psi-mi:“MI:0915”(physical association)	0.720
KLHL35	APPBP2	psi-mi:“MI:0915”(physical association)	0.720
ALAS1	KLHL35	psi-mi:“MI:0915”(physical association)	0.680
KLHL35	ALAS1	psi-mi:“MI:0915”(physical association)	0.680
GOLGA6L9	KLHL35	psi-mi:“MI:0915”(physical association)	0.560
CALCOCO2	KLHL35	psi-mi:“MI:0915”(physical association)	0.560
KLHL35	UBTD2	psi-mi:“MI:0915”(physical association)	0.560
NCK2	KLHL35	psi-mi:“MI:0915”(physical association)	0.560
FAM25C	KLHL35	psi-mi:“MI:0915”(physical association)	0.560
NUDCD3	KLHL35	psi-mi:“MI:0915”(physical association)	0.400
KLHL35	APPBP2	psi-mi:“MI:0915”(physical association)	0.000
KLHL35	GOLGA6L9	psi-mi:“MI:0915”(physical association)	0.000
KLHL35	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.000
UBTD2	KLHL35	psi-mi:“MI:0915”(physical association)	0.000
NCK2	KLHL35	psi-mi:“MI:0915”(physical association)	0.000
KLHL35	FAM25C	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): KLHL35 (Two-hybrid), KLHL35 (Two-hybrid), KLHL35 (Two-hybrid), KLHL35 (PCA), KLHL35 (Two-hybrid), KLHL35 (Two-hybrid), KLHL35 (Two-hybrid), UBTD2 (Two-hybrid), FAM25A (Two-hybrid), FAM25G (Two-hybrid), GOLGA6L9 (Two-hybrid), FAM25C (Two-hybrid)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A4FV98, A6QPA3, C9J798, C9JJ37, D3YWP0, D3ZVU9, D4A2K4, O43374, O70277, O75382, O95294, P0C6S8, P22674, P57775, Q08DS0, Q0GA42, Q3U410, Q3UGX3, Q4G0W2, Q4V892, Q5SUV1, Q5XIU1, Q6GQU6, Q6IA17, Q6PF15, Q6TDP3, Q6TDP4, Q7TNM2, Q7Z4K8, Q86WI3, Q8CIW5, Q8IZ69, Q8K430, Q8N531, Q8N8L6, Q8NE01, Q8WXI3, Q969K4

Diamond homologs: A2APT9, A6NCF5, C9JR72, O94819, Q2T9Z7, Q5R866, Q5RDY3, Q5VTJ3, Q5ZLD3, Q6PF15, Q6ZPT1, Q8BFQ9, Q8BGY4, Q8BNW9, Q8C3F7, Q8C828, Q920Q8, Q96G42, Q9P2J3, Q9P2K6, A0A2R8Q1W5, B0WWP2, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, D4A2K4, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, F1LZF0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	142
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

827 predictions. Top by Δscore:

Variant	Effect	Δscore
11:75422764:CTTTC:C	acceptor_gain	1.0000
11:75422769:C:A	acceptor_loss	1.0000
11:75422769:C:CC	acceptor_gain	1.0000
11:75422770:T:A	acceptor_loss	1.0000
11:75423734:G:A	donor_gain	1.0000
11:75425388:CCCA:C	donor_loss	1.0000
11:75425390:CACCT:C	donor_loss	1.0000
11:75425392:CCTT:C	donor_loss	1.0000
11:75429744:CCTAC:C	donor_loss	1.0000
11:75429748:C:CA	donor_loss	1.0000
11:75429750:T:TA	donor_gain	1.0000
11:75422765:TTTC:T	acceptor_gain	0.9900
11:75422767:TC:T	acceptor_gain	0.9900
11:75422768:CC:C	acceptor_gain	0.9900
11:75422773:G:C	acceptor_gain	0.9900
11:75422773:G:GC	acceptor_gain	0.9900
11:75422778:C:CT	acceptor_gain	0.9900
11:75423685:CACTT:C	donor_loss	0.9900
11:75423686:ACTT:A	donor_loss	0.9900
11:75423687:CTT:C	donor_loss	0.9900
11:75423688:TTA:T	donor_loss	0.9900
11:75423689:TAC:T	donor_loss	0.9900
11:75423690:A:AC	donor_gain	0.9900
11:75423691:C:CC	donor_gain	0.9900
11:75423691:CCA:C	donor_gain	0.9900
11:75423878:CAC:C	acceptor_gain	0.9900
11:75423882:T:C	acceptor_loss	0.9900
11:75425416:G:A	donor_gain	0.9900
11:75425444:G:A	donor_gain	0.9900
11:75425579:CAG:C	acceptor_gain	0.9900

AlphaMissense

3729 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:75426585:A:G	W374R	0.997
11:75426585:A:T	W374R	0.997
11:75425506:A:G	W421R	0.993
11:75425506:A:T	W421R	0.993
11:75429961:C:A	W223C	0.993
11:75429961:C:G	W223C	0.993
11:75430454:A:T	L59H	0.993
11:75428447:A:T	V354D	0.992
11:75430441:G:C	S63R	0.992
11:75430441:G:T	S63R	0.992
11:75430443:T:G	S63R	0.992
11:75425504:C:A	W421C	0.991
11:75425504:C:G	W421C	0.991
11:75429963:A:G	W223R	0.991
11:75429963:A:T	W223R	0.991
11:75430310:A:T	L107H	0.990
11:75430433:A:G	F66S	0.990
11:75430468:G:C	C54W	0.990
11:75423724:A:G	W511R	0.989
11:75423724:A:T	W511R	0.989
11:75423850:A:G	W469R	0.989
11:75423850:A:T	W469R	0.989
11:75429992:T:A	E213V	0.989
11:75429875:A:G	F252S	0.988
11:75430467:G:C	H55D	0.988
11:75430469:C:T	C54Y	0.988
11:75425527:A:C	Y414D	0.987
11:75425561:G:C	F402L	0.986
11:75425561:G:T	F402L	0.986
11:75425563:A:G	F402L	0.986

dbSNP variants (sampled 300 via entrez): RS1000001078 (11:75426460 C>G,T), RS1000280427 (11:75426692 C>A,T), RS1000788689 (11:75433730 C>T), RS1000842286 (11:75430322 A>G), RS1000905085 (11:75433511 G>C,T), RS1001130706 (11:75427438 A>G), RS1001299251 (11:75430432 G>C,T), RS1001500375 (11:75423508 G>A,C), RS1001732178 (11:75428966 G>A,T), RS1001788960 (11:75435188 G>A), RS1001899265 (11:75429621 C>G), RS1001903426 (11:75434918 C>T), RS1002016030 (11:75429229 T>C), RS1002018237 (11:75434223 C>T), RS1003475434 (11:75425747 C>G,T)

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

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects methylation, increases abundance	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
afuresertib	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
ferrous chloride	decreases expression	1
entinostat	decreases expression	1
ICG 001	increases expression	1
jinfukang	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, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Vorinostat	decreases expression	1
Vehicle Emissions	affects methylation, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Ozone	affects methylation, increases abundance	1
Plant Extracts	decreases expression, affects cotreatment	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	affects expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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