KLHDC8A

Summary

KLHDC8A (kelch domain containing 8A, HGNC:25573) is a protein-coding gene on chromosome 1q32.1, encoding Kelch domain-containing protein 8A (Q8IYD2).

This gene encodes a kelch domain-containing protein which is upregulated in cancer. Upregulated expression of the encoded protein may provide an alternative pathway for tumors to maintain aggressiveness in the absence of epidermal growth factor receptor dependence. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55220 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 58 total
• MANE Select transcript: NM_018203

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25573
Approved symbol	KLHDC8A
Name	kelch domain containing 8A
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10748
Ensembl gene	ENSG00000162873
Ensembl biotype	protein_coding
OMIM	614503
Entrez	55220

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 27 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000367155, ENST00000367156, ENST00000460687, ENST00000491471, ENST00000539253, ENST00000606111, ENST00000606181, ENST00000606529, ENST00000606887, ENST00000607173, ENST00000607193, ENST00000607826, ENST00000900187, ENST00000900188, ENST00000941896, ENST00000941897, ENST00000941898, ENST00000941899, ENST00000941900, ENST00000941901, ENST00000941902, ENST00000941903, ENST00000941904, ENST00000941905, ENST00000941906, ENST00000941907, ENST00000941908, ENST00000941909, ENST00000941910, ENST00000941911

RefSeq mRNA: 4 — MANE Select: NM_018203 NM_001271863, NM_001271864, NM_001271865, NM_018203

CCDS: CCDS30985

Canonical transcript exons

ENST00000367155 — 6 exons

Exon	Start	End
ENSE00001443648	205356533	205356922
ENSE00001443651	205343229	205343793
ENSE00003665475	205339644	205339808
ENSE00003694878	205339194	205339409
ENSE00003697098	205338495	205338596
ENSE00003900970	205336061	205337592

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 97.90.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0016 / max 235.5479, expressed in 271 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16982	0.6620	88
16984	0.5989	150
16981	0.1542	64
16983	0.1364	63
16975	0.1104	51
16977	0.0514	15
16973	0.0486	23
16978	0.0458	11
16972	0.0442	15
16985	0.0399	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	97.90	gold quality
ovary	UBERON:0000992	95.34	gold quality
right ovary	UBERON:0002118	94.21	gold quality
right uterine tube	UBERON:0001302	93.83	gold quality
germinal epithelium of ovary	UBERON:0001304	92.66	gold quality
ganglionic eminence	UBERON:0004023	91.36	gold quality
right adrenal gland cortex	UBERON:0035827	89.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.65	gold quality
ventricular zone	UBERON:0003053	89.48	gold quality
cerebellar hemisphere	UBERON:0002245	89.40	gold quality
cerebellar cortex	UBERON:0002129	89.26	gold quality
left adrenal gland cortex	UBERON:0035825	89.15	gold quality
right adrenal gland	UBERON:0001233	89.13	gold quality
adrenal cortex	UBERON:0001235	88.85	gold quality
cerebellum	UBERON:0002037	87.99	gold quality
left adrenal gland	UBERON:0001234	87.72	gold quality
endothelial cell	CL:0000115	85.62	gold quality
adrenal gland	UBERON:0002369	84.86	gold quality
islet of Langerhans	UBERON:0000006	84.15	gold quality
pons	UBERON:0000988	84.03	gold quality
adenohypophysis	UBERON:0002196	83.58	gold quality
left uterine tube	UBERON:0001303	83.48	gold quality
embryo	UBERON:0000922	82.46	gold quality
pituitary gland	UBERON:0000007	82.37	gold quality
hypothalamus	UBERON:0001898	81.55	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.63	gold quality
nucleus accumbens	UBERON:0001882	80.06	gold quality
cortical plate	UBERON:0005343	79.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.31	gold quality
superior vestibular nucleus	UBERON:0007227	77.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting KLHDC8A, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-3616-5P	99.55	67.02	989

Literature-anchored findings (GeneRIF, showing 3)

• Upregulation of KLHDC8A provides an alternative pathway for xenograft tumors to maintain aggressiveness in the absence of EGFR dependence. (PMID:20133782)
• Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling. (PMID:36394953)
• [miRNA-128-3p inhibits malignant behavior of glioma cells by downregulating KLHDC8A expression]. (PMID:37814858)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klhdc8a	ENSMUSG00000042115
rattus_norvegicus	Klhdc8a	ENSRNOG00000000036

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), 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 domain-containing protein 8A — Q8IYD2 (reviewed: Q8IYD2)

Alternative names: Substitute for delta-EGFR expression 1

All UniProt accessions (7): Q8IYD2, U3KPW1, U3KPX9, U3KQC2, U3KQH1, U3KQI4, U3KQK4

RefSeq proteins (4): NP_001258792, NP_001258793, NP_001258794, NP_060673* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006652	Kelch_1	Repeat
IPR011043	Gal_Oxase/kelch_b-propeller	Homologous_superfamily
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR051746	Kelch_domain_containing_8	Family

Pfam: PF01344, PF24681

UniProt features (9 total): repeat 7, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYD2-F1	95.62	0.93

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 98 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, TCF4_Q5, SHEN_SMARCA2_TARGETS_DN, HEB_Q6, MEISSNER_NPC_HCP_WITH_H3K4ME3_AND_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K4ME3_AND_H3K27ME3, MARTENS_TRETINOIN_RESPONSE_UP, VERHAAK_GLIOBLASTOMA_CLASSICAL, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B, BRUINS_UVC_RESPONSE_LATE, KATSANOU_ELAVL1_TARGETS_DN, PLASARI_TGFB1_TARGETS_10HR_UP, IL2_UP.V1_DN, IL21_UP.V1_DN, KRAS.KIDNEY_UP.V1_DN

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

578 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHDC8A	TMEM71	Q6P5X7	496
KLHDC8A	CCDC18	Q5T9S5	477
KLHDC8A	GMPPA	Q96IJ6	471
KLHDC8A	RAB42	Q8N4Z0	443
KLHDC8A	WSCD1	Q658N2	431
KLHDC8A	PRRT4	C9JH25	417
KLHDC8A	KLHDC4	Q8TBB5	388
KLHDC8A	LRRC10B	A6NIK2	387
KLHDC8A	RNFT2	Q96EX2	384
KLHDC8A	C5orf15	Q8NC54	370
KLHDC8A	GAS2L3	Q86XJ1	359
KLHDC8A	LRRC28	Q86X40	354
KLHDC8A	FAM234A	Q9H0X4	353
KLHDC8A	PHYKPL	Q8IUZ5	348
KLHDC8A	GNG5	P30670	336

IntAct

6 interactions, top by confidence:

A	B	Type	Score
NUDCD3	KLHDC8A	psi-mi:“MI:0915”(physical association)	0.670
KLHDC8A	PEX7	psi-mi:“MI:0914”(association)	0.530
KLHDC8A	TCP1	psi-mi:“MI:0914”(association)	0.530
NUDC	KLHDC8A	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (33): CCT6B (Affinity Capture-MS), LONP1 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), PDCL (Affinity Capture-MS), TXNDC9 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), PSME3 (Affinity Capture-MS), PEX7 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), PPP2CA (Affinity Capture-MS)

ESM2 similar proteins: A2AAX3, A6QQY2, D3ZA50, G3X9X1, Q0IIC2, Q28DE7, Q2TBA3, Q2WGJ6, Q3KRE6, Q3MHH0, Q4G5Y1, Q4R3J7, Q4V8F4, Q56A24, Q58CV6, Q5BK60, Q5E9A7, Q5EA50, Q5RDA9, Q5RDY3, Q5RGB8, Q5U3Y0, Q5U580, Q5ZJ37, Q5ZJU2, Q63ZP7, Q6AYI2, Q6DEL7, Q6P809, Q6PAR0, Q6PID8, Q6TFL4, Q7Z6M1, Q80TF4, Q80WC9, Q80YG3, Q8AYC9, Q8BGZ3, Q8BRG6, Q8BSF5

Diamond homologs: A6QQY2, Q0WW40, Q2WGJ6, Q5BK60, Q5R866, Q5VTJ3, Q5ZLD3, Q6ZPT1, Q80TF4, Q8BSF5, Q8IYD2, Q91XA8, Q93W93, Q9CAG8, Q9D783, Q9FFV5, Q9P2N7, Q9SH13, Q5E9V5, Q5RCW7, Q5XIA9, Q8IXV7, Q8N239, Q9D2D9, O14682, Q4KLM4, Q6DFF7, Q8R2P1, Q9H0H3, Q0D2A9, Q6NRH0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1292 predictions. Top by Δscore:

Variant	Effect	Δscore
1:205339170:T:TA	donor_gain	1.0000
1:205339189:CTCA:C	donor_loss	1.0000
1:205339190:TCA:T	donor_loss	1.0000
1:205339191:CA:C	donor_loss	1.0000
1:205339192:A:AC	donor_gain	1.0000
1:205339192:A:AT	donor_loss	1.0000
1:205339192:AC:A	donor_gain	1.0000
1:205339193:C:CC	donor_gain	1.0000
1:205339193:CC:C	donor_gain	1.0000
1:205339418:C:CT	acceptor_gain	1.0000
1:205337589:TTCC:T	acceptor_gain	0.9900
1:205337591:CC:C	acceptor_gain	0.9900
1:205337592:CC:C	acceptor_gain	0.9900
1:205337594:T:G	acceptor_loss	0.9900
1:205337599:G:C	acceptor_gain	0.9900
1:205338592:TCCCC:T	acceptor_gain	0.9900
1:205338593:CCCC:C	acceptor_gain	0.9900
1:205338593:CCCCC:C	acceptor_gain	0.9900
1:205338594:CCC:C	acceptor_gain	0.9900
1:205338594:CCCC:C	acceptor_gain	0.9900
1:205338595:CCC:C	acceptor_gain	0.9900
1:205339193:CCCT:C	donor_gain	0.9900
1:205339193:CCCTG:C	donor_gain	0.9900
1:205339214:T:TA	donor_gain	0.9900
1:205339407:CCC:C	acceptor_gain	0.9900
1:205339408:CC:C	acceptor_gain	0.9900
1:205339408:CCC:C	acceptor_gain	0.9900
1:205339409:CC:C	acceptor_gain	0.9900
1:205339409:CCT:C	acceptor_loss	0.9900
1:205339411:T:C	acceptor_loss	0.9900

AlphaMissense

2265 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:205339347:A:G	W202R	1.000
1:205339347:A:T	W202R	1.000
1:205339722:A:G	W155R	1.000
1:205339722:A:T	W155R	1.000
1:205338500:C:T	G285E	0.999
1:205338503:C:T	G284E	0.999
1:205338504:C:A	G284W	0.999
1:205338591:A:G	W255R	0.999
1:205338591:A:T	W255R	0.999
1:205339228:G:C	F241L	0.999
1:205339228:G:T	F241L	0.999
1:205339230:A:G	F241L	0.999
1:205339268:C:T	G228E	0.999
1:205339309:G:C	F214L	0.999
1:205339309:G:T	F214L	0.999
1:205339311:A:G	F214L	0.999
1:205343286:A:G	W107R	0.999
1:205343286:A:T	W107R	0.999
1:205343352:C:A	G85W	0.999
1:205343430:A:G	W59R	0.999
1:205343430:A:T	W59R	0.999
1:205343574:A:G	W11R	0.999
1:205343574:A:T	W11R	0.999
1:205337536:A:G	W306R	0.998
1:205337536:A:T	W306R	0.998
1:205338500:C:A	G285V	0.998
1:205338501:C:G	G285R	0.998
1:205338501:C:T	G285R	0.998
1:205338551:C:G	R268P	0.998
1:205339265:C:T	G229D	0.998

dbSNP variants (sampled 300 via entrez): RS1000218840 (1:205354620 G>A), RS1000257355 (1:205338576 G>A,T), RS1000350199 (1:205338256 C>T), RS1000411588 (1:205344301 G>A), RS1000450132 (1:205336888 C>A), RS1000501874 (1:205337284 T>C), RS1000569234 (1:205338592 T>A,C), RS1000572069 (1:205340189 A>G,T), RS1000615214 (1:205344070 G>T), RS1000683637 (1:205345428 T>C), RS1000865751 (1:205344538 G>C), RS1000916816 (1:205349528 A>G), RS1001030750 (1:205349755 G>A), RS1001168410 (1:205345770 C>T), RS1001252765 (1:205347988 T>C)

Disease associations

OMIM: gene MIM:614503 | 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
GCST010002_349	Refractive error	8.000000e-13
GCST010143_9	Meat-related diet	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	affects cotreatment, decreases expression, increases expression	3
methylmercuric chloride	decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
propionaldehyde	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Arsenic Trioxide	increases expression	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression, increases abundance	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Niclosamide	increases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1

Clinical trials (associated diseases)

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