KLHL33

Summary

KLHL33 (kelch like family member 33, HGNC:31952) is a protein-coding gene on chromosome 14q11.2, encoding Kelch-like protein 33 (A6NCF5).

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 117 total — 1 pathogenic
• MANE Select transcript: NM_001365790

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31952
Approved symbol	KLHL33
Name	kelch like family member 33
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000185271
Ensembl biotype	protein_coding
Entrez	123103

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000344581, ENST00000636854, ENST00000637228

RefSeq mRNA: 2 — MANE Select: NM_001365790 NM_001109997, NM_001365790

CCDS: CCDS53882, CCDS91847

Canonical transcript exons

ENST00000636854 — 5 exons

Exon	Start	End
ENSE00001321340	20429502	20429669
ENSE00003793327	20429795	20430719
ENSE00003794152	20425852	20429401
ENSE00003817671	20435064	20435830
ENSE00003821791	20436099	20436166

Expression profiles

Bgee: expression breadth ubiquitous, 112 present calls, max score 88.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0687 / max 21.7390, expressed in 13 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142025	0.0362	11
207136	0.0173	9
142026	0.0152	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue	UBERON:0001134	88.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.02	gold quality
muscle of leg	UBERON:0001383	82.60	gold quality
gastrocnemius	UBERON:0001388	81.69	gold quality
muscle tissue	UBERON:0002385	79.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.13	gold quality
gall bladder	UBERON:0002110	58.40	gold quality
apex of heart	UBERON:0002098	58.31	gold quality
heart left ventricle	UBERON:0002084	57.89	gold quality
body of uterus	UBERON:0009853	57.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	57.22	gold quality
lower esophagus	UBERON:0013473	57.18	gold quality
smooth muscle tissue	UBERON:0001135	56.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	56.72	gold quality
right atrium auricular region	UBERON:0006631	56.70	gold quality
heart	UBERON:0000948	56.03	gold quality
lymph node	UBERON:0000029	55.36	gold quality
endocervix	UBERON:0000458	55.18	gold quality
myometrium	UBERON:0001296	55.01	gold quality
uterine cervix	UBERON:0000002	54.52	gold quality
right coronary artery	UBERON:0001625	54.16	gold quality
urinary bladder	UBERON:0001255	54.08	gold quality
muscle layer of sigmoid colon	UBERON:0035805	54.05	gold quality
colonic epithelium	UBERON:0000397	53.96	gold quality
calcaneal tendon	UBERON:0003701	53.95	silver quality
ovary	UBERON:0000992	53.91	gold quality
tibial nerve	UBERON:0001323	53.78	gold quality
right ovary	UBERON:0002118	53.70	gold quality
cerebellum	UBERON:0002037	53.63	gold quality
cerebellar cortex	UBERON:0002129	53.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.22

Regulation

Is transcription factor: no

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000113137
mus_musculus	Klhl33	ENSMUSG00000090799
rattus_norvegicus	Klhl33	ENSRNOG00000025868

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), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

Kelch-like protein 33 — A6NCF5 (reviewed: A6NCF5)

All UniProt accessions (3): A6NCF5, A0A1B0GTK0, A0A1B0GUB7

RefSeq proteins (2): NP_001103467, NP_001352719* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
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
IPR030609	KLHL33_BACK	Domain

Pfam: PF01344, PF07707, PF21536, PF24681

UniProt features (11 total): repeat 6, sequence variant 4, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NCF5-F1	90.82	0.76

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 9 (showing top): MISIAK_ANAPLASTIC_THYROID_CARCINOMA_UP, FEST_POST_ACTIVATED_B_CELL_CD23_UP, GENES_CORRELATED_WITH_BRAF_DELETION, GSE8921_UNSTIM_0H_VS_TLR1_2_STIM_MONOCYTE_24H_UP, GSE19941_UNSTIM_VS_LPS_STIM_IL10_KO_MACROPHAGE_DN, GSE27859_MACROPHAGE_VS_DC_DN, chr14q11, GSE40685_NAIVE_CD4_TCELL_VS_FOXP3_KO_TREG_PRECURSOR_UP, GSE35543_IN_VIVO_NTREG_VS_IN_VITRO_ITREG_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

534 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL33	PM20D2	Q8IYS1	515
KLHL33	C3orf22	Q8N5N4	478
KLHL33	NT5C1A	Q9BXI3	454
KLHL33	RNASE12	Q5GAN4	446
KLHL33	SMIM17	P0DL12	431
KLHL33	C12orf56	Q8IXR9	430
KLHL33	UBR3	Q6ZT12	419
KLHL33	SH2D7	A6NKC9	399
KLHL33	CC2D2B	Q6DHV5	396
KLHL33	DUSP22	Q9NRW4	396
KLHL33	C1orf167	Q5SNV9	395
KLHL33	C22orf42	Q6IC83	395
KLHL33	ANKRD62	A6NC57	393
KLHL33	TRIM55	Q9BYV6	382
KLHL33	CLPSL1	A2RUU4	379

IntAct

5 interactions, top by confidence:

A	B	Type	Score
KLHL33	HSPD1	psi-mi:“MI:0914”(association)	0.530
KLHL33	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
KLHL33	BAG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (37): TUBB1 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), CCT6A (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), CCT8 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS)

ESM2 similar proteins: A1A5C7, A5D7B1, A6H7A0, A6NCF5, A6QLN9, A8MUP2, D3YYU8, D3ZZ80, O43688, O75147, O88843, P08887, Q14CX5, Q3SZQ2, Q3UHH2, Q58CT4, Q5EA19, Q5R4Q7, Q5R7S9, Q5RCI5, Q5RFN0, Q5SP67, Q5SUV1, Q642A6, Q6IA17, Q6PCB0, Q7TPB4, Q86TI4, Q8BGR6, Q8BZI6, Q8K5A4, Q8N5I2, Q8N653, Q8R2Z5, Q8TBF2, Q8VE98, Q92737, Q969P0, Q96NJ5, Q96NT3

Diamond homologs: A2APT9, A6NCF5, C9JR72, O94819, Q2T9Z7, Q5R866, Q5RDY3, Q5VTJ3, Q5ZLD3, Q6PF15, Q6ZPT1, Q8BFQ9, Q8BGY4, Q8BNW9, Q8C3F7, Q8C828, Q920Q8, Q96G42, Q9P2J3, Q9P2K6, Q25386, Q3ZB90, Q5U575, Q6GQU2, Q9C6Z0, Q9SVA0, D4A2K4, G3X9X1, O35709, Q08DS0, Q0D2A9, Q0D2K2, Q14145, Q1ECZ2, Q3U410, Q53G59, Q53HC5, Q5R774, Q5RG82, Q5U374

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	108
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
395470	GRCh37/hg19 14q11.2-32.33(chr14:19794561-107234280)x3	Pathogenic

SpliceAI

632 predictions. Top by Δscore:

Variant	Effect	Δscore
14:20429497:CTTA:C	donor_loss	1.0000
14:20429498:TTACC:T	donor_loss	1.0000
14:20429499:TA:T	donor_loss	1.0000
14:20429500:A:AC	donor_gain	1.0000
14:20429500:ACC:A	donor_loss	1.0000
14:20429500:ACCT:A	donor_gain	1.0000
14:20429501:C:CA	donor_loss	1.0000
14:20429501:C:CC	donor_gain	1.0000
14:20429501:CCT:C	donor_gain	1.0000
14:20429501:CCTC:C	donor_gain	1.0000
14:20430165:C:CA	donor_gain	1.0000
14:20435461:CACCT:C	donor_gain	1.0000
14:20435465:T:TA	donor_gain	1.0000
14:20429503:T:TA	donor_gain	0.9900
14:20429665:CCCAC:C	acceptor_gain	0.9900
14:20429666:CCAC:C	acceptor_gain	0.9900
14:20429666:CCACC:C	acceptor_gain	0.9900
14:20429667:CAC:C	acceptor_gain	0.9900
14:20429667:CACC:C	acceptor_gain	0.9900
14:20429677:CAG:C	acceptor_gain	0.9900
14:20429678:A:T	acceptor_gain	0.9900
14:20429679:G:C	acceptor_gain	0.9900
14:20429679:G:GC	acceptor_gain	0.9900
14:20430563:G:A	donor_gain	0.9900
14:20430605:AGGT:A	donor_gain	0.9900
14:20430608:T:TA	donor_gain	0.9900
14:20435471:T:TA	donor_gain	0.9900
14:20429402:C:CC	acceptor_gain	0.9800
14:20429668:AC:A	acceptor_gain	0.9800
14:20429669:CC:C	acceptor_gain	0.9800

AlphaMissense

5064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20429928:A:G	W250R	0.988
14:20429928:A:T	W250R	0.988
14:20429329:G:C	S374R	0.987
14:20429329:G:T	S374R	0.987
14:20429331:T:G	S374R	0.987
14:20429926:C:A	W250C	0.983
14:20429926:C:G	W250C	0.983
14:20428971:A:G	W494R	0.982
14:20428971:A:T	W494R	0.982
14:20430191:A:T	V162D	0.982
14:20429506:A:G	W349R	0.976
14:20429506:A:T	W349R	0.976
14:20429504:C:A	W349C	0.973
14:20429504:C:G	W349C	0.973
14:20429843:C:T	G278E	0.972
14:20429645:C:A	W302C	0.971
14:20429645:C:G	W302C	0.971
14:20429647:A:G	W302R	0.970
14:20429647:A:T	W302R	0.970
14:20428969:C:A	W494C	0.966
14:20428969:C:G	W494C	0.966
14:20429890:G:C	F262L	0.966
14:20429890:G:T	F262L	0.966
14:20429892:A:G	F262L	0.966
14:20429844:C:A	G278W	0.965
14:20430586:A:C	F30L	0.964
14:20430586:A:T	F30L	0.964
14:20430588:A:G	F30L	0.964
14:20430176:A:G	M167T	0.963
14:20429574:G:T	A326D	0.959

dbSNP variants (sampled 300 via entrez): RS1000056255 (14:20437894 C>G,T), RS1000160718 (14:20433642 TA>T,TAA), RS1000296203 (14:20433392 A>G), RS1000349835 (14:20432309 C>T), RS1000674490 (14:20434025 T>C,G), RS1000934275 (14:20433741 T>C), RS1001194308 (14:20428594 C>T), RS1001676263 (14:20435405 C>G,T), RS1001770180 (14:20432989 A>G), RS1002071611 (14:20433292 G>A,T), RS1002503916 (14:20437449 A>G), RS1002545835 (14:20425494 T>C), RS1002644783 (14:20437209 G>A), RS1002814579 (14:20427327 T>C), RS1002948496 (14:20427096 A>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

2 associations (top):

Study	Trait	p-value
GCST003489_7	Food addiction	7.000000e-07
GCST006984_4	Takayasu arteritis	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007829	eating behaviour
EFO:0007830	food addiction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases methylation	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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