RNF139

Summary

RNF139 (ring finger protein 139, HGNC:17023) is a protein-coding gene on chromosome 8q24.13, encoding E3 ubiquitin-protein ligase RNF139 (Q8WU17). E3-ubiquitin ligase; acts as a negative regulator of cell proliferation through mechanisms involving G2/M arrest and cell death.

The protein encoded by this gene is a multi-membrane spanning protein containing a RING-H2 finger. This protein is located in the endoplasmic reticulum, and has been shown to possess ubiquitin ligase activity. This gene was found to be interrupted by a t(3:8) translocation in a family with hereditary renal and non-medulary thyroid cancer. Studies of the Drosophila counterpart suggested that this protein may interact with tumor suppressor protein VHL, as well as with COPS5/JAB1, a protein responsible for the degradation of tumor suppressor CDKN1B/P27KIP.

Source: NCBI Gene 11236 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonpapillary renal cell carcinoma (Limited, GenCC)
• Clinical variants (ClinVar): 74 total — 1 pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_007218

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17023
Approved symbol	RNF139
Name	ring finger protein 139
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Aliases	TRC8, RCA1, HRCA1
Ensembl gene	ENSG00000170881
Ensembl biotype	protein_coding
OMIM	603046
Entrez	11236

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000303545, ENST00000517684, ENST00000716592

RefSeq mRNA: 1 — MANE Select: NM_007218 NM_007218

CCDS: CCDS6350

Canonical transcript exons

ENST00000303545 — 2 exons

Exon	Start	End
ENSE00001165789	124485831	124488618
ENSE00004030202	124474880	124475290

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.2561 / max 274.4448, expressed in 1812 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90502	14.3362	1794
90501	7.3058	1734
90503	4.8927	1637
90504	1.6392	654
90505	0.0821	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.14	gold quality
male germ cell	CL:0000015	97.64	gold quality
left testis	UBERON:0004533	96.08	gold quality
right testis	UBERON:0004534	95.90	gold quality
endothelial cell	CL:0000115	95.29	gold quality
testis	UBERON:0000473	94.97	gold quality
adult organism	UBERON:0007023	94.66	gold quality
parietal pleura	UBERON:0002400	94.54	gold quality
pleura	UBERON:0000977	94.04	gold quality
visceral pleura	UBERON:0002401	93.13	gold quality
cartilage tissue	UBERON:0002418	92.99	gold quality
cauda epididymis	UBERON:0004360	92.81	gold quality
adrenal tissue	UBERON:0018303	92.58	gold quality
synovial joint	UBERON:0002217	92.51	gold quality
calcaneal tendon	UBERON:0003701	92.14	gold quality
tendon	UBERON:0000043	91.93	gold quality
monocyte	CL:0000576	91.92	gold quality
mononuclear cell	CL:0000842	91.89	gold quality
tendon of biceps brachii	UBERON:0008188	91.81	gold quality
leukocyte	CL:0000738	91.77	gold quality
parotid gland	UBERON:0001831	91.61	gold quality
biceps brachii	UBERON:0001507	91.56	gold quality
skin of hip	UBERON:0001554	91.51	gold quality
placenta	UBERON:0001987	91.18	gold quality
islet of Langerhans	UBERON:0000006	91.10	gold quality
oral cavity	UBERON:0000167	91.07	gold quality
tibia	UBERON:0000979	91.00	gold quality
epithelium of nasopharynx	UBERON:0001951	90.78	gold quality
decidua	UBERON:0002450	90.71	gold quality
epithelium of mammary gland	UBERON:0003244	90.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

115 targeting RNF139, 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-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972

Literature-anchored findings (GeneRIF, showing 12)

• TRC8 modulation of sterol response element binding protein activity comprises a novel regulatory link between growth control and the cholesterol/lipid homeostasis pathway. (PMID:17016439)
• The presence of diploid and tetraploid tumor cells with and without TRC8 deletions on the nontranslocated chromosome suggest that loss of the remaining normal allele of TRC8 may contribute to tumor development at later stages. (PMID:17539022)
• TRC8 is a novel sterol-sensing endoplasmic reticulum membrane protein that hinders SREBP-2 processing through interaction with SREBP-2 and SCAP, regulating its own turnover rate by means of its E3 ubiquitin ligase activity (PMID:19706601)
• Data show that the TRC8 E3 ligase is required for MHC I dislocation from the ER and identify a new complex associated with mammalian ERAD. (PMID:19720873)
• TRC8 function may provide a regulatory link between the lipid and protein biosynthetic pathways. (PMID:20068067)
• TRC8 suppresses tumorigenesis through targeting heme oxygenase-1 for ubiquitination and degradation. (PMID:22689053)
• TRC8 and TMEM129 are endoplasmic reticulum-associated degradation ubiquitin E3 ligases for viral and cellular targeting of MHC class I. (Review) (PMID:26210183)
• interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening (PMID:27998983)
• Low RNF139 expression is associated with progression of tongue cancer. (PMID:28662643)
• TRC8 and MARCH6 depletion altered the turnover of the tail-anchored protein heme oxygenase-1. (PMID:29519897)
• INSIG1 coordinated with another ligase, translocation in renal carcinoma chromosome 8 (TRC8), and promoted Gag degradation through the lysosome pathway. (PMID:30563842)
• An E3 Ubiquitin Ligase RNF139 Serves as a Tumor-Suppressor in Glioma. (PMID:34106407)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf139	ENSDARG00000036929
mus_musculus	Rnf139	ENSMUSG00000037075
rattus_norvegicus	Ndufb9	ENSRNOG00000008987
drosophila_melanogaster	Trc8	FBGN0039668

Paralogs (4): RNF145 (ENSG00000145860), AMFR (ENSG00000159461), SYVN1 (ENSG00000162298), DZIP3 (ENSG00000198919)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF139 — Q8WU17 (reviewed: Q8WU17)

Alternative names: RING finger protein 139, RING-type E3 ubiquitin transferase RNF139, Translocation in renal carcinoma on chromosome 8 protein

All UniProt accessions (2): Q8WU17, E5RH85

UniProt curated annotations — full annotation on UniProt →

Function. E3-ubiquitin ligase; acts as a negative regulator of cell proliferation through mechanisms involving G2/M arrest and cell death. Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER). Affects SREBP processing by hindering the SREBP-SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression. Involved in the sterol-accelerated degradation of HMGCR. This is achieved through binding of RNF139 to INSIG1 and/or INSIG2 at the ER membrane. In addition, interaction of RNF139 with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR, leading to ubiquitination of HMGCR. The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction. Required for INSIG1 ubiquitination. May be required for EIF3 complex ubiquitination.

Subunit / interactions. Interacts with MHC class I and HM13. Interacts with VHL. Component of SCAP-SREBP complex composed of SREBF2, SCAP and RNF139; the complex hampers the interaction between SCAP and SEC24B, thereby reducing SREBF2 proteolytic processing. Interacts with SREBF2 (via C-terminal domain). Interacts with SCAP; the interaction inhibits the interaction of SCAP with SEC24B and hampering the ER to Golgi transport of the SCAP-SREBP complex. Interacts with SEC24B. Interacts with INSIG1 and INSIG2. Interacts with EIF3F and EIF3H; the interaction leads to protein translation inhibitions in a ubiquitination-dependent manner. Interacts with XBP1 isoform 1; the interaction induces ubiquitination and degradation of XBP1 isoform 1. Interacts with AUP1, AMFR and UBE2G2; interaction with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR/gp78, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Highly expressed in testis, placenta and adrenal gland. Moderate expression in heart, brain, liver, skeletal muscle and pancreas, and low expression in lung and kidney.

Post-translational modifications. Autoubiquitinated. Ubiquitination is induced by sterol and leads to ist degradation via the ubiquitin-proteasome pathway.

Disease relevance. Renal cell carcinoma (RCC) [MIM:144700] Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. The disease may be caused by variants affecting the gene represented in this entry. A chromosomal aberration involving RNF139 has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation (3;8)(q14.2;q24.1) with FHIT. RNF139 is found to be fused to FHIT and disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. Sporadic cases of renal carcinoma, where an acquired mutation in RNF139 results in the duplication of 12 nucleotides in the 5’-UTR, has also been identified.

Domain organisation. The RING-type zinc finger domain mediates ubiquitin ligase activity.

Induction. Down-regulated by sterols (at protein level).

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_009149* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR011016	Znf_RING-CH	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR025754	TRC8_N_dom	Domain
IPR050731	HRD1_E3_ubiq-ligases	Family

Pfam: PF13639, PF13705

UniProt features (28 total): transmembrane region 12, mutagenesis site 5, modified residue 4, compositionally biased region 2, initiator methionine 1, chain 1, zinc finger region 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WU17-F1	79.88	0.29

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 (4): 2, 634, 635, 663

Mutagenesis-validated functional residues (5):

Position	Phenotype
547–586	increases proliferation. rescues mhc class i to the cell surface. fails to down-regulate srebf1 and srebf2.
547–550	abolishes ubiquitination activity. increases proliferation. does not phosphorylate chek2 on t-68. does not phosphorylate
557–559	retaines about 30% of ubiquitination activity.
572–574	abolishes ubiquitination activity. increases proliferation.
582–585	abolishes ubiquitination activity. increases proliferation.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-901032	ER Quality Control Compartment (ERQC)
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-597592	Post-translational protein modification
R-HSA-901042	Calnexin/calreticulin cycle

MSigDB gene sets: 249 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, TTCCGTT_MIR191, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, ATACCTC_MIR202, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, AATGGAG_MIR136, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (10): negative regulation of cell population proliferation (GO:0008285), protein ubiquitination (GO:0016567), negative regulation of translation (GO:0017148), protein destabilization (GO:0031648), ERAD pathway (GO:0036503), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of ER to Golgi vesicle-mediated transport (GO:0060628), regulation of protein processing (GO:0070613), endoplasmic reticulum mannose trimming (GO:1904380), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060)

GO Molecular Function (9): protease binding (GO:0002020), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin-like protein transferase activity (GO:0019787), signaling receptor activity (GO:0038023), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020), Derlin-1 retrotranslocation complex (GO:0036513), endoplasmic reticulum quality control compartment (GO:0044322)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Calnexin/calreticulin cycle	1
Post-translational protein modification	1
Asparagine N-linked glycosylation	1
Metabolism of proteins	1
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
proteasomal protein catabolic process	2
ubiquitin-dependent protein catabolic process	2
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
protein modification by small protein conjugation	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
regulation of protein stability	1
response to endoplasmic reticulum stress	1
response to chemical	1
endoplasmic reticulum to Golgi vesicle-mediated transport	1
regulation of intracellular transport	1
regulation of vesicle-mediated transport	1
protein processing	1
regulation of proteolysis	1
regulation of protein maturation	1
protein alpha-1,2-demannosylation	1
endoplasmic reticulum quality control compartment	1
positive regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
enzyme binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
molecular transducer activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1

Protein interactions and networks

STRING

1026 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF139	HM13	Q8TCT9	980
RNF139	USH2A	O75445	932
RNF139	UBE2G2	P56554	784
RNF139	INSIG2	Q9Y5U4	780
RNF139	MARCHF6	O60337	756
RNF139	RNF5	Q99942	755
RNF139	SEL1L	Q9UBV2	750
RNF139	SREBF2	Q12772	749
RNF139	INSIG1	O15503	733
RNF139	TMEM129	A0AVI4	721
RNF139	ERLEC1	Q96DZ1	704
RNF139	OS9	Q13438	702
RNF139	DIRC1	Q969H9	685
RNF139	COPS5	Q92905	665
RNF139	DERL1	Q9BUN8	655

IntAct

24 interactions, top by confidence:

A	B	Type	Score
ATXN1	RNF139	psi-mi:“MI:0915”(physical association)	0.560
HM13	RNF139	psi-mi:“MI:0915”(physical association)	0.520
LY6G6D	HSPA5	psi-mi:“MI:0914”(association)	0.500
XBP1	RNF139	psi-mi:“MI:0915”(physical association)	0.400
ERLIN2	RNF139	psi-mi:“MI:0915”(physical association)	0.400
RNF139	TMUB1	psi-mi:“MI:0915”(physical association)	0.400
VHL	RNF139	psi-mi:“MI:0915”(physical association)	0.400
RNF139	VHL	psi-mi:“MI:0915”(physical association)	0.400
RNF139	UBE2U	psi-mi:“MI:0915”(physical association)	0.370
RNF139	UBE2Z	psi-mi:“MI:0915”(physical association)	0.370
RNF139	UBE2H	psi-mi:“MI:0915”(physical association)	0.370
CFTR	RNF139	psi-mi:“MI:0915”(physical association)	0.370
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC2A7	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): RNF139 (Affinity Capture-Western), RNF139 (Affinity Capture-Western), RNF139 (PCA), INSIG1 (Affinity Capture-Western), RNF139 (Positive Genetic), RNF139 (Affinity Capture-MS), VDAC1 (Affinity Capture-MS), CCDC47 (Affinity Capture-MS), SIGMAR1 (Affinity Capture-MS), TMEM165 (Affinity Capture-MS), EPHX1 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), ADPGK (Affinity Capture-MS), KIAA2013 (Affinity Capture-MS), CLPTM1L (Affinity Capture-MS)

ESM2 similar proteins: A0A061ACU2, A8WWR3, B0YA61, F1RAX4, F4IN58, G5EBX4, M9MSG8, O13909, O42901, O45813, O74475, O74520, O74949, O94543, O94599, P34535, P38837, P40528, P53224, P90859, Q01608, Q06144, Q0U2R3, Q0V9G6, Q10287, Q12013, Q19293, Q20332, Q4WCL2, Q54TM2, Q5F3W2, Q5RBT7, Q5ZIU0, Q60M68, Q6DF80, Q6NVQ1, Q7TMV1, Q7YWX7, Q80UA9, Q8AV61

Diamond homologs: A5WWA0, A8Y4B2, E9QAU8, O00237, O22197, O22283, O43085, O54965, O55176, O64763, P0CH03, P0CH30, P0DPR2, P87119, P90859, Q08CG8, Q08D68, Q0II22, Q2KHN1, Q3T0W3, Q3U2C5, Q3UHJ8, Q4KLR8, Q4V7B8, Q566M8, Q5DTZ6, Q5M974, Q5QLR5, Q5RBT7, Q5SPX3, Q5SSZ7, Q5XHH7, Q66HG0, Q6AXU4, Q6DIP3, Q6GPV5, Q6IRP0, Q6NPT7, Q6NRL6, Q6NRX0

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF139	ubiquitination
RNF139	“down-regulates quantity”	INSIG1	ubiquitination
RNF139	“down-regulates quantity”	INSIG2	ubiquitination
RNF139	“down-regulates quantity”	SREBF1	ubiquitination
RNF139	“down-regulates quantity”	SREBF2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	70
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3024645	GRCh37/hg19 8q23.3-24.3(chr8:113392581-146364022)x3	Pathogenic

SpliceAI

306 predictions. Top by Δscore:

Variant	Effect	Δscore
8:124485826:TTTA:T	acceptor_loss	1.0000
8:124485828:TAGG:T	acceptor_loss	1.0000
8:124485829:A:AG	acceptor_gain	1.0000
8:124485829:A:AT	acceptor_loss	1.0000
8:124485830:G:GG	acceptor_gain	1.0000
8:124485830:GGT:G	acceptor_gain	1.0000
8:124485830:GGTGT:G	acceptor_gain	1.0000
8:124475288:TTGG:T	donor_loss	0.9900
8:124475290:GGTA:G	donor_loss	0.9900
8:124475291:G:GG	donor_gain	0.9900
8:124475291:GT:G	donor_loss	0.9900
8:124475292:T:TC	donor_loss	0.9900
8:124485829:AG:A	acceptor_gain	0.9900
8:124485829:AGGT:A	acceptor_gain	0.9900
8:124485830:GG:G	acceptor_gain	0.9900
8:124485830:GGTG:G	acceptor_gain	0.9900
8:124477263:T:G	donor_gain	0.9700
8:124483372:A:AG	donor_gain	0.9700
8:124477258:T:G	donor_gain	0.9400
8:124485827:TTAGG:T	acceptor_gain	0.9400
8:124485828:TAGGT:T	acceptor_gain	0.9400
8:124485829:A:C	acceptor_gain	0.9400
8:124485830:G:T	acceptor_gain	0.9400
8:124477262:A:AG	donor_gain	0.9200
8:124475283:GCTCT:G	donor_gain	0.9000
8:124474953:G:T	donor_gain	0.8800
8:124475306:AC:A	donor_gain	0.8600
8:124475307:CC:C	donor_gain	0.8600
8:124485826:TTTAG:T	acceptor_gain	0.8600
8:124475288:TTG:T	donor_gain	0.8500

AlphaMissense

4345 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:124486925:T:C	F426L	1.000
8:124486927:T:A	F426L	1.000
8:124486927:T:G	F426L	1.000
8:124487214:G:C	R522P	1.000
8:124487223:C:A	A525D	1.000
8:124487288:T:A	C547S	1.000
8:124487288:T:C	C547R	1.000
8:124487289:G:A	C547Y	1.000
8:124487289:G:C	C547S	1.000
8:124487290:T:G	C547W	1.000
8:124487295:T:A	I549N	1.000
8:124487297:T:C	C550R	1.000
8:124487298:G:A	C550Y	1.000
8:124487299:C:G	C550W	1.000
8:124487336:T:C	C563R	1.000
8:124487337:G:A	C563Y	1.000
8:124487338:T:G	C563W	1.000
8:124487344:T:A	H565Q	1.000
8:124487344:T:G	H565Q	1.000
8:124487348:T:C	F567L	1.000
8:124487350:C:A	F567L	1.000
8:124487350:C:G	F567L	1.000
8:124487360:T:A	C571S	1.000
8:124487360:T:C	C571R	1.000
8:124487361:G:A	C571Y	1.000
8:124487361:G:C	C571S	1.000
8:124487362:C:G	C571W	1.000
8:124487364:T:A	L572H	1.000
8:124487364:T:C	L572P	1.000
8:124487372:T:A	W575R	1.000

dbSNP variants (sampled 300 via entrez): RS1000269539 (8:124482785 G>A,C), RS1000278197 (8:124488316 G>A), RS1000468819 (8:124480437 T>A,C), RS1000627619 (8:124481974 A>G), RS1000922223 (8:124475348 G>C,T), RS1000943069 (8:124475955 T>C), RS1000995249 (8:124475646 G>T), RS1001154203 (8:124483421 TTTTTA>T), RS1001196091 (8:124482230 C>G), RS1001298614 (8:124483899 T>C,G), RS1002237702 (8:124481393 A>G), RS1002250455 (8:124474697 A>G), RS1002408987 (8:124474915 C>G,T), RS1002630798 (8:124485209 C>A,G,T), RS1002897551 (8:124478262 C>T)

Disease associations

OMIM: gene MIM:603046 | disease phenotypes: MIM:144700

GenCC curated gene-disease

Disease	Classification	Inheritance
nonpapillary renal cell carcinoma	Limited	Autosomal dominant

Mondo (1): nonpapillary renal cell carcinoma (MONDO:0007763)

Orphanet (1): Hereditary clear cell renal cell carcinoma (Orphanet:422526)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0003745	Sporadic
HP:0005584	Renal cell carcinoma

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

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
jinfukang	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Catechin	affects cotreatment, increases expression	1
Coal	decreases expression, increases abundance	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Piroxicam	decreases expression	1
Progesterone	affects cotreatment, decreases expression	1
Testosterone	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases methylation	1
Aflatoxin M1	decreases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00033904	PHASE3	COMPLETED	Survival Study Of Oncophage® vs. Observation In Patients With Kidney Cancer
NCT00126178	PHASE3	TERMINATED	Clinical Trial Studying a Personalized Cancer Vaccine in Patients With Non-metastatic Kidney Cancer
NCT00291369	PHASE3	COMPLETED	Cytokines in Patients With Metastatic Renal Cell Carcinoma of Intermediate Prognosis
NCT00326898	PHASE3	COMPLETED	Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery
NCT00410124	PHASE3	COMPLETED	RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib
NCT00474786	PHASE3	COMPLETED	Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib
NCT00478114	PHASE3	COMPLETED	Efficacy and Safety of Sorafenib in Advanced Renal Cell Carcinoma (RCC)
NCT00606632	PHASE3	COMPLETED	Pre-surgical Detection of Clear Cell Renal Cell Carcinoma (ccRCC) Using Radiolabeled G250-Antibody
NCT00606866	PHASE3	COMPLETED	MRI Study of BAY 43-9006 in Metastatic Renal Cell Carcinoma
NCT00631371	PHASE3	COMPLETED	Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects
NCT00732914	PHASE3	COMPLETED	Sequential Study to Treat Renal Cell Carcinoma
NCT00869011	PHASE3	UNKNOWN	Exercise for Patients With Renal Cell Cancer Receiving Sunitinib
NCT00930033	PHASE3	COMPLETED	Clinical Trial to Assess the Importance of Nephrectomy
NCT01030783	PHASE3	COMPLETED	A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
NCT01076010	PHASE3	COMPLETED	An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).
NCT01198158	PHASE3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01223027	PHASE3	COMPLETED	Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma
NCT01224288	PHASE3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01235962	PHASE3	COMPLETED	A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC)
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01265901	PHASE3	COMPLETED	IMA901 in Patients Receiving Sunitinib for Advanced/Metastatic Renal Cell Carcinoma
NCT01481870	PHASE3	UNKNOWN	Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
NCT01575548	PHASE3	ACTIVE_NOT_RECRUITING	Pazopanib Hydrochloride in Treating Patients With Metastatic Kidney Cancer Who Have No Evidence of Disease After Surgery
NCT01582672	PHASE3	TERMINATED	Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma
NCT01613846	PHASE3	COMPLETED	Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)
NCT01762592	PHASE3	WITHDRAWN	REDECT 2: REnal Masses: Pivotal Trial to DEteCT Clear Cell Renal Cell Carcinoma With PET/CT
NCT01865747	PHASE3	COMPLETED	A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma
NCT02231749	PHASE3	COMPLETED	Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)