RNF166

Summary

RNF166 (ring finger protein 166, HGNC:28856) is a protein-coding gene on chromosome 16q24.2-q24.3, encoding E3 ubiquitin-protein ligase RNF166 (Q96A37). E3 ubiquitin-protein ligase that promotes the ubiquitination of different substrates.

Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein polyubiquitination and ubiquitin-dependent protein catabolic process. Predicted to be located in cytoplasm.

Source: NCBI Gene 115992 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 57 total — 1 pathogenic
• MANE Select transcript: NM_178841

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28856
Approved symbol	RNF166
Name	ring finger protein 166
Location	16q24.2-q24.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC2647, MGC14381
Ensembl gene	ENSG00000158717
Ensembl biotype	protein_coding
OMIM	617178
Entrez	115992

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000312838, ENST00000537718, ENST00000541206, ENST00000562499, ENST00000562544, ENST00000564894, ENST00000565083, ENST00000567408, ENST00000567844, ENST00000568683, ENST00000569478, ENST00000878562, ENST00000956472

RefSeq mRNA: 3 — MANE Select: NM_178841 NM_001171815, NM_001171816, NM_178841

CCDS: CCDS10969, CCDS54056, CCDS54057

Canonical transcript exons

ENST00000312838 — 6 exons

Exon	Start	End
ENSE00001040570	88698502	88698609
ENSE00001113713	88698971	88699085
ENSE00001291940	88696501	88697633
ENSE00001304570	88706171	88706408
ENSE00003526620	88701262	88701418
ENSE00003567118	88699620	88699732

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1488 / max 402.6642, expressed in 1798 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158570	18.0621	1790
158564	2.1039	261
158565	0.6640	178
158566	0.5204	130
158568	0.3311	109
158567	0.2402	87
158569	0.1143	47
158563	0.1128	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.22	gold quality
monocyte	CL:0000576	97.05	gold quality
leukocyte	CL:0000738	97.04	gold quality
spleen	UBERON:0002106	97.00	gold quality
blood	UBERON:0000178	95.91	gold quality
bone marrow cell	CL:0002092	94.92	gold quality
vermiform appendix	UBERON:0001154	94.80	gold quality
upper lobe of left lung	UBERON:0008952	93.87	gold quality
right lung	UBERON:0002167	93.79	gold quality
upper lobe of lung	UBERON:0008948	92.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.65	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.34	gold quality
lymph node	UBERON:0000029	92.33	gold quality
gall bladder	UBERON:0002110	91.51	gold quality
cerebellar hemisphere	UBERON:0002245	91.42	gold quality
left uterine tube	UBERON:0001303	91.22	gold quality
cerebellar cortex	UBERON:0002129	91.19	gold quality
right coronary artery	UBERON:0001625	90.57	gold quality
omental fat pad	UBERON:0010414	90.35	gold quality
peritoneum	UBERON:0002358	90.27	gold quality
right uterine tube	UBERON:0001302	90.18	gold quality
right ovary	UBERON:0002118	89.82	gold quality
tibial nerve	UBERON:0001323	89.80	gold quality
small intestine	UBERON:0002108	89.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.37	gold quality
cerebellum	UBERON:0002037	89.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.16	gold quality
body of stomach	UBERON:0001161	89.12	gold quality
right lobe of liver	UBERON:0001114	89.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting RNF166, 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-23B-5P	99.98	66.07	587
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-4676-5P	97.54	65.29	715
HSA-MIR-575	97.54	65.18	718
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-4445-5P	97.21	66.16	832
HSA-MIR-424-3P	97.20	65.86	385
HSA-MIR-7975	95.04	66.76	516

Literature-anchored findings (GeneRIF, showing 5)

• These findings suggest that RNF166 positively regulates RNA virus-triggered IFN-beta production by enhancing the ubiquitination of TRAF3 and TRAF6. (PMID:26456228)
• An unbiased informatics approach pinpointed RNF166 as a key gene that interacts with the autophagy network and controls the recruitment of ubiquitin as well as the autophagy adaptors p62 and NDP52 to bacteria. (PMID:27880896)
• Podocyte RNF166 deficiency alleviates diabetic nephropathy by mitigating mitochondria impairment and apoptosis via regulation of CYLD signal. (PMID:33545631)
• RNF166 plays a dual role for Lys63-linked ubiquitination and sumoylation of its target proteins. (PMID:34837535)
• RNF166 promotes colorectal cancer progression by recognizing and destabilizing poly-ADP-ribosylated angiomotins. (PMID:38480683)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf166	ENSDARG00000089538
mus_musculus	Rnf166	ENSMUSG00000014470
rattus_norvegicus	Rnf166	ENSRNOG00000013777

Paralogs (4): RNF125 (ENSG00000101695), RNF114 (ENSG00000124226), RNF138 (ENSG00000134758), RNF180 (ENSG00000164197)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF166 — Q96A37 (reviewed: Q96A37)

Alternative names: RING finger protein 166, RING-type E3 ubiquitin transferase RNF166

All UniProt accessions (4): Q96A37, H3BPZ9, H3BQ58, H3BTX7

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that promotes the ubiquitination of different substrates. In turn, participates in different biological processes including interferon production or autophagy. Plays a role in the activation of RNA virus-induced interferon-beta production by promoting the ubiquitination of TRAF3 and TRAF6. Also plays a role in the early recruitment of autophagy adapters to bacteria. Mediates ‘Lys-29’ and ‘Lys-33’-linked ubiquitination of SQSTM1 leading to xenophagic targeting of bacteria and inhibition of their replication.

Subcellular location. Cytoplasm.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96A37-1	1	yes
Q96A37-2	2
Q96A37-3	3

RefSeq proteins (3): NP_001165286, NP_001165287, NP_849163* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR008598	Di19_Zn-bd	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR027370	Znf-RING_euk	Domain
IPR034734	ZF_C2HC_RNF	Domain
IPR051438	RNF_E3_ubiq-protein_ligase	Family

Pfam: PF05605, PF13445, PF18574

UniProt features (15 total): binding site 4, sequence conflict 3, mutagenesis site 2, zinc finger region 2, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96A37-F1	84.93	0.65

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 98; 101; 113; 117

Mutagenesis-validated functional residues (2):

Position	Phenotype
33	complete loss of sqstm1 ubiquitination; in association with a-36.
36	complete loss of sqstm1 ubiquitination; in association with a-33.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 132 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CAGCTG_AP4_Q5, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, ATF3_Q6, CREB_Q2_01, ATF_01, GOBP_PROTEIN_CATABOLIC_PROCESS, GAVIN_FOXP3_TARGETS_CLUSTER_P3, GOBP_PROTEOLYSIS, GOTTWEIN_TARGETS_OF_KSHV_MIR_K12_11, GOMF_ACYLTRANSFERASE_ACTIVITY

GO Biological Process (6): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), autophagy (GO:0006914), innate immune response (GO:0045087), immune system process (GO:0002376), protein ubiquitination (GO:0016567)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
modification-dependent protein catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
immune response	1
defense response to symbiont	1
biological_process	1
protein modification by small protein conjugation	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF166	LRSAM1	Q6UWE0	699
RNF166	KLHL28	Q9NXS3	676
RNF166	ZBTB39	O15060	646
RNF166	ZNF653	Q96CK0	637
RNF166	ZNF827	Q17R98	588
RNF166	FBXO28	Q9NVF7	584
RNF166	ZNF692	Q9BU19	550
RNF166	MAGEE2	Q8TD90	549
RNF166	ZNRD2	O60232	543
RNF166	ZFP91	Q96JP5	540
RNF166	ZNF276	Q8N554	479
RNF166	PIEZO1	Q92508	472
RNF166	ZC3HC1	Q86WB0	444
RNF166	ZNF69	Q9UC07	435
RNF166	CORO7	P57737	429

IntAct

78 interactions, top by confidence:

A	B	Type	Score
RNF166	UBE2D4	psi-mi:“MI:0915”(physical association)	0.670
XAF1	RNF166	psi-mi:“MI:0915”(physical association)	0.670
XAF1	AKT1	psi-mi:“MI:0914”(association)	0.670
UBE2K	RNF166	psi-mi:“MI:0915”(physical association)	0.560
PRKN	RNF166	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	RNF166	psi-mi:“MI:0915”(physical association)	0.560
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
LTBR	ZNF724	psi-mi:“MI:0914”(association)	0.530
TNFAIP3	UBB	psi-mi:“MI:0914”(association)	0.530
RNF166	MPDZ	psi-mi:“MI:0914”(association)	0.530
PLPPR1	STXBP3	psi-mi:“MI:0914”(association)	0.530
C11orf24	NME2P1	psi-mi:“MI:0914”(association)	0.530
PARP12	GCLM	psi-mi:“MI:0914”(association)	0.530
CLEC4E	TUBB3	psi-mi:“MI:0914”(association)	0.530
TMEM192	STXBP3	psi-mi:“MI:0914”(association)	0.530
TNFRSF13B	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
APOC2	APOE	psi-mi:“MI:0914”(association)	0.530

BioGRID (157): RNF166 (Affinity Capture-MS), RNF166 (Affinity Capture-MS), CENPF (Affinity Capture-MS), PARP1 (Affinity Capture-MS), LIG1 (Affinity Capture-MS), HLTF (Affinity Capture-MS), NUP98 (Affinity Capture-MS), TNKS2 (Affinity Capture-MS), TNKS (Affinity Capture-MS), AMOTL1 (Affinity Capture-MS), AMOT (Affinity Capture-MS), TJP1 (Affinity Capture-MS), INADL (Affinity Capture-MS), MPDZ (Affinity Capture-MS), HERC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A974CYQ5, A5WW08, A7XUJ6, B5DF45, B6CJY4, B6CJY5, O00463, O15344, O70583, P0DW87, P0DW89, P39429, P53351, P70191, P70196, P82457, P82458, Q08CH8, Q12933, Q13114, Q28DL4, Q29RQ5, Q2TAD9, Q3KPU8, Q3MV19, Q3U9F6, Q3ZCC3, Q5FWP4, Q5R4L1, Q60803, Q61382, Q6DJN2, Q6GNX1, Q6IWL4, Q6J1I7, Q6P256, Q80WG7, Q8N2W9, Q91ZY8, Q969K3

Diamond homologs: A5D7F8, A5D8S5, G3X8Y1, H0UZ81, O60858, Q28E95, Q32L60, Q38HM4, Q3KPU8, Q3U9F6, Q58D15, Q5F3B2, Q5PQN5, Q5RBR0, Q5REJ9, Q5XIH6, Q69ZI1, Q6J1I7, Q6NRD3, Q71F54, Q7Z6J0, Q8C120, Q8TEJ3, Q91Z63, Q969Q1, Q96A37, Q99PJ2, Q9BRZ2, Q9BYV2, Q9BYV6, Q9BZR9, Q9ERP3, A0JN74, A6NK02, B1H278, B6VQ60, D3YY23, P15919, P33288, P34088

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF166	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	9	66.3×	1e-12
Negative regulators of DDX58/IFIH1 signaling	6	39.1×	1e-06
Regulation of TNFR1 signaling	5	22.4×	2e-04
E3 ubiquitin ligases ubiquitinate target proteins	5	19.4×	4e-04
Antigen processing: Ubiquitination & Proteasome degradation	18	13.4×	1e-13

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	7	41.6×	7e-08
protein monoubiquitination	6	31.3×	5e-06
protein K48-linked ubiquitination	11	28.1×	1e-10
protein polyubiquitination	11	19.2×	4e-09
ubiquitin-dependent protein catabolic process	10	11.2×	3e-06
protein ubiquitination	12	7.5×	6e-06
proteasome-mediated ubiquitin-dependent protein catabolic process	8	6.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	51
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
267481	Single allele	Pathogenic

SpliceAI

1474 predictions. Top by Δscore:

Variant	Effect	Δscore
16:88698970:CCACG:C	donor_gain	1.0000
16:88699045:CACAG:C	acceptor_gain	1.0000
16:88699081:TGTTG:T	acceptor_gain	1.0000
16:88699082:GTTG:G	acceptor_gain	1.0000
16:88699083:TTG:T	acceptor_gain	1.0000
16:88699616:CTA:C	donor_loss	1.0000
16:88699732:CCTAG:C	acceptor_loss	1.0000
16:88699733:CTA:C	acceptor_loss	1.0000
16:88699734:T:A	acceptor_loss	1.0000
16:88701257:GGTAC:G	donor_loss	1.0000
16:88701258:GTAC:G	donor_loss	1.0000
16:88701259:TACCT:T	donor_loss	1.0000
16:88701260:A:C	donor_loss	1.0000
16:88706169:A:AC	donor_gain	1.0000
16:88706170:C:CC	donor_gain	1.0000
16:88698496:GCCT:G	donor_loss	0.9900
16:88698497:CCTA:C	donor_loss	0.9900
16:88698498:CTACC:C	donor_loss	0.9900
16:88698499:TA:T	donor_loss	0.9900
16:88698500:A:AC	donor_gain	0.9900
16:88698501:C:CA	donor_loss	0.9900
16:88698501:C:CC	donor_gain	0.9900
16:88698501:CCA:C	donor_gain	0.9900
16:88698606:ACACC:A	acceptor_loss	0.9900
16:88698607:CAC:C	acceptor_gain	0.9900
16:88698608:ACCT:A	acceptor_loss	0.9900
16:88698609:CCT:C	acceptor_loss	0.9900
16:88698610:CTGG:C	acceptor_loss	0.9900
16:88698611:TGGAA:T	acceptor_loss	0.9900
16:88698933:C:A	donor_gain	0.9900

AlphaMissense

1552 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:88698520:G:C	F210L	1.000
16:88698520:G:T	F210L	1.000
16:88698521:A:G	F210S	1.000
16:88698522:A:G	F210L	1.000
16:88698526:G:C	H208Q	1.000
16:88698526:G:T	H208Q	1.000
16:88698528:G:C	H208D	1.000
16:88698528:G:T	H208N	1.000
16:88698530:C:G	R207P	1.000
16:88698539:A:G	L204P	1.000
16:88698541:G:C	H203Q	1.000
16:88698541:G:T	H203Q	1.000
16:88698543:G:C	H203D	1.000
16:88698543:G:T	H203N	1.000
16:88698551:A:G	F200S	1.000
16:88698578:C:T	G191E	1.000
16:88698579:C:A	G191W	1.000
16:88698579:C:G	G191R	1.000
16:88698579:C:T	G191R	1.000
16:88698580:C:A	W190C	1.000
16:88698580:C:G	W190C	1.000
16:88698582:A:G	W190R	1.000
16:88698582:A:T	W190R	1.000
16:88698595:G:C	C185W	1.000
16:88698596:C:A	C185F	1.000
16:88698596:C:G	C185S	1.000
16:88698596:C:T	C185Y	1.000
16:88698597:A:G	C185R	1.000
16:88698597:A:T	C185S	1.000
16:88698604:G:C	C182W	1.000

dbSNP variants (sampled 300 via entrez): RS1000040633 (16:88706261 C>G,T), RS1000079824 (16:88703274 A>C), RS1000143981 (16:88708407 G>A,T), RS1000384739 (16:88703797 C>G), RS1000433889 (16:88701800 G>A,C), RS1000674828 (16:88704583 C>G,T), RS1000689997 (16:88701174 G>C,T), RS1000766771 (16:88704437 T>G), RS1001151337 (16:88698789 C>T), RS1001321147 (16:88703828 G>A), RS1001375714 (16:88707053 C>G,T), RS1001452762 (16:88704806 A>G), RS1001607900 (16:88702028 G>A), RS1001628489 (16:88703929 C>T), RS1002058620 (16:88698290 G>A)

Disease associations

OMIM: gene MIM:617178 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): 16q24.3 microdeletion syndrome (MONDO:0016838)

Orphanet (1): 16q24.3 microdeletion syndrome (Orphanet:261250)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003479_9	Hair color	1.000000e-07
GCST008526_17	Coffee consumption	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006781	coffee consumption measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Nickel	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Thalidomide	increases degradation, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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