RNF125

Summary

RNF125 (ring finger protein 125, HGNC:21150) is a protein-coding gene on chromosome 18q12.1, encoding E3 ubiquitin-protein ligase RNF125 (Q96EQ8). E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins, such as RIGI, MAVS/IPS1, IFIH1/MDA5, JAK1 and p53/TP53.

This gene encodes a novel E3 ubiquitin ligase that contains a RING finger domain in the N-terminus and three zinc-binding and one ubiquitin-interacting motif in the C-terminus. As a result of myristoylation, this protein associates with membranes and is primarily localized to intracellular membrane systems. The encoded protein may function as a positive regulator in the T-cell receptor signaling pathway.

Source: NCBI Gene 54941 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tenorio syndrome (Strong, GenCC)
• Clinical variants (ClinVar): 88 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_017831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21150
Approved symbol	RNF125
Name	ring finger protein 125
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20456
Ensembl gene	ENSG00000101695
Ensembl biotype	protein_coding
OMIM	610432
Entrez	54941

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000217740, ENST00000580209, ENST00000580863, ENST00000583384, ENST00000583814, ENST00000718283, ENST00000718284, ENST00000909753

RefSeq mRNA: 1 — MANE Select: NM_017831 NM_017831

CCDS: CCDS11902

Canonical transcript exons

ENST00000217740 — 6 exons

Exon	Start	End
ENSE00000916043	32018825	32019027
ENSE00001279677	32068298	32073219
ENSE00003470044	32065902	32066009
ENSE00003552777	32042179	32042273
ENSE00003673254	32037116	32037269
ENSE00003675464	32045642	32045732

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 95.50.

FANTOM5 (CAGE): breadth broad, TPM avg 11.9120 / max 650.2482, expressed in 658 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169857	10.9512	591
169856	0.4246	176
169848	0.3537	141
169849	0.1543	74
169860	0.0282	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.50	gold quality
oocyte	CL:0000023	93.95	gold quality
secondary oocyte	CL:0000655	91.94	gold quality
parietal pleura	UBERON:0002400	91.29	gold quality
pleura	UBERON:0000977	88.25	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.09	gold quality
superficial temporal artery	UBERON:0001614	86.50	gold quality
colonic mucosa	UBERON:0000317	86.27	gold quality
visceral pleura	UBERON:0002401	86.27	gold quality
jejunum	UBERON:0002115	86.19	gold quality
leukocyte	CL:0000738	85.73	gold quality
monocyte	CL:0000576	85.64	gold quality
mononuclear cell	CL:0000842	85.48	gold quality
inferior vagus X ganglion	UBERON:0005363	84.71	gold quality
upper leg skin	UBERON:0004262	84.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.82	gold quality
skin of hip	UBERON:0001554	83.27	gold quality
duodenum	UBERON:0002114	83.27	gold quality
granulocyte	CL:0000094	83.24	gold quality
trigeminal ganglion	UBERON:0001675	82.03	gold quality
nipple	UBERON:0002030	81.85	gold quality
subthalamic nucleus	UBERON:0001906	81.72	gold quality
blood	UBERON:0000178	81.40	gold quality
adipose tissue	UBERON:0001013	81.15	gold quality
calcaneal tendon	UBERON:0003701	80.73	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.45	gold quality
connective tissue	UBERON:0002384	80.39	gold quality
thoracic mammary gland	UBERON:0005200	80.26	gold quality
bone marrow	UBERON:0002371	80.14	gold quality
mammary gland	UBERON:0001911	80.10	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	531.47
E-ANND-3	yes	10.29
E-GEOD-110499	no	625.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

163 targeting RNF125, 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-12118	100.00	65.88	1270
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705

Literature-anchored findings (GeneRIF, showing 14)

• These results suggest that RNF125/TRAC-1 could function to recruit host factor(s) controlling HIV-1 transcription to the ubiquitin-proteasome pathway. (PMID:17643463)
• TRAC-1 associates with membranes and is excluded from the nucleus through myristoylation (PMID:17990982)
• study reports human bocavirus VP2 modulates IFN pathway by targeting the ring finger protein 125, a negative regulator of type I IFN signaling, which conjugates Lys(48)-linked ubiquitination to retinoic acid-inducible gene-I and leads to the proteasome-dependent degradation of RIG-I (PMID:23772026)
• In controls, RNF125 is the highest expressed gene, whereas in HIV infection progressors, RIG-I is either the highest expressed gene or is expressed similarly to RNF125 and TRIM25. (PMID:24131985)
• studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors (PMID:25196541)
• we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas (PMID:26027934)
• Results indicate that the nucleotide sequence in the 3’ untranslated region (3’ UTR) of ring finger protein 125 (RNF125) is a potential microRNA miR-15b targeting site. (PMID:26202983)
• for the ubiquitin ligase RNF125 that, in addition to the RING domain, a C2HC Zn finger (ZnF) is crucial for activity. (PMID:27411375)
• study identifies new gene-type zinc finger protein 125 (RNF125) as a negative regulator of TRIM14 in the innate antiviral immune response (PMID:28476934)
• high RNF125 expression is related with aggressive characteristics and unfavorable prognosis of GBC patients; RNF125 promotes the invasion and metastasis of human GBCs via activating the TGF-beta1-SMAD3-ID1 signaling pathway. (PMID:28611292)
• this study shows that RNF125 activates Interleukin-36 receptor signaling and contributes to its turnover (PMID:29176319)
• G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral response. (PMID:31827077)
• E3 Ubiquitin Ligase RNF125 Suppresses Immune Escape in Head and Neck Squamous Cell Carcinoma by Regulating PD-L1 Expression. (PMID:36344734)
• RNF125 attenuates hepatocellular carcinoma progression by downregulating SRSF1-ERK pathway. (PMID:37142680)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rnf125	ENSMUSG00000033107
rattus_norvegicus	Rnf125	ENSRNOG00000057832

Paralogs (4): RNF114 (ENSG00000124226), RNF138 (ENSG00000134758), RNF166 (ENSG00000158717), RNF180 (ENSG00000164197)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF125 — Q96EQ8 (reviewed: Q96EQ8)

Alternative names: RING finger protein 125, T-cell RING activation protein 1

All UniProt accessions (2): Q96EQ8, J3QQW8

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins, such as RIGI, MAVS/IPS1, IFIH1/MDA5, JAK1 and p53/TP53. Acts as a negative regulator of type I interferon production by mediating ubiquitination of RIGI at ‘Lys-181’, leading to RIGI degradation. Mediates ubiquitination and subsequent degradation of p53/TP53. Mediates ubiquitination and subsequent degradation of JAK1. Acts as a positive regulator of T-cell activation.

Subunit / interactions. Interacts with UBE2D1. Interacts with VCP/p97; leading to recruit RNF125 to RIGI and promote ubiquitination of RIGI.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Predominantly expressed in lymphoid tissues, including bone marrow, spleen and thymus. Also weakly expressed in other tissues. Predominant in the CD4(+) and CD8(+) T-cells, suggesting that it is preferentially confined to T-cells.

Post-translational modifications. Autoubiquitinated, leading to its subsequent proteasomal degradation.

Disease relevance. Tenorio syndrome (TNORS) [MIM:616260] A disease characterized by overgrowth, macrocephaly, and intellectual disability. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C2HC RNF-type zinc finger and the linker region stabilize the RING-type zinc finger, leading to promote binding of the RING-type zinc finger to the ubiquitin-conjugating enzyme E2 (donor ubiquitin).

Induction. Down-regulated by miR-15b. Down-regulated in BRAFi resistant melanomas, leading to increased levels of JAK1 and possibly promoting BRAFi resistance.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_060301* (*=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
IPR034734	ZF_C2HC_RNF	Domain
IPR051438	RNF_E3_ubiq-protein_ligase	Family

Pfam: PF05605, PF13923, PF18574

UniProt features (53 total): binding site 12, mutagenesis site 11, region of interest 5, strand 5, helix 5, sequence variant 3, sequence conflict 3, turn 3, zinc finger region 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5DKA	X-RAY DIFFRACTION	1.55
8GBQ	X-RAY DIFFRACTION	1.74
8GCB	X-RAY DIFFRACTION	2.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EQ8-F1	77.90	0.40

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 (12): 37; 40; 52; 54; 57; 60; 72; 75; 100; 103; 115; 119

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (11):

Position	Phenotype
2	abolishes ability to regulate t-cell activation but not e3 ligase activity in vitro. also abolishes myristoylation and m
37	abolishes ability to regulate t-cell activation and e3 ligase activity in vitro; when associated with a-40.
40	abolishes ability to regulate t-cell activation and e3 ligase activity in vitro; when associated with a-37.
54	abolishes ability to regulate t-cell activation and e3 ligase activity in vitro; when associated with a-57.
57	abolishes ability to regulate t-cell activation and e3 ligase activity in vitro; when associated with a-54.
72	abolishes ability to regulate t-cell activation and e3 ligase activity in vitro; when associated with a-75.
75	abolishes ability to regulate t-cell activation and e3 ligase activity in vitro; when associated with a-72.
100–103	abolished e3 ubiquitin-protein ligase activity in vitro.
109–113	abolished e3 ubiquitin-protein ligase activity in vitro.
217	reduced ubiquitination and reduced binding to ubiquitinated proteins; when associated with q-221.
221	reduced ubiquitination and reduced binding to ubiquitinated proteins; when associated with p-217.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta

MSigDB gene sets: 345 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, REACTOME_INNATE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GGGTGGRR_PAX4_03, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, chr18q12, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_CYTOKINE_PRODUCTION

GO Biological Process (8): protein polyubiquitination (GO:0000209), adaptive immune response (GO:0002250), ubiquitin-dependent protein catabolic process (GO:0006511), negative regulation of type I interferon production (GO:0032480), negative regulation of RIG-I signaling pathway (GO:0039536), cellular response to leukemia inhibitory factor (GO:1990830), immune system process (GO:0002376), protein ubiquitination (GO:0016567)

GO Molecular Function (8): p53 binding (GO:0002039), zinc ion binding (GO:0008270), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): Golgi membrane (GO:0000139), VCP-NPL4-UFD1 AAA ATPase complex (GO:0034098), intracellular membrane-bounded organelle (GO:0043231), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Immune System	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
intracellular anatomical structure	2
cellular anatomical structure	2
immune response	1
modification-dependent protein catabolic process	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
RIG-I signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
regulation of RIG-I signaling pathway	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
biological_process	1
protein modification by small protein conjugation	1
protein binding	1
transition metal ion binding	1
ubiquitin-like protein conjugating enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
Golgi apparatus	1
bounding membrane of organelle	1
endoplasmic reticulum membrane	1
UFD1-NPL4 complex	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
membrane-bounded organelle	1
intracellular organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3069 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF125	RIGI	O95786	832
RNF125	TRIM25	Q14258	831
RNF125	IFIH1	Q9BYX4	803
RNF125	DHX58	Q96C10	760
RNF125	MAVS	Q7Z434	757
RNF125	RNF135	Q8IUD6	714
RNF125	RNF122	Q9H9V4	679
RNF125	UBE2L6	O14933	668
RNF125	ISG15	P05161	651
RNF125	TRIM4	Q9C037	591
RNF125	UBE2D1	P51668	576
RNF125	RNF5	Q99942	553
RNF125	MEX3C	Q5U5Q3	546
RNF125	G3V2F7	G3V2F7	540
RNF125	CYLD	Q9NQC7	538

IntAct

39 interactions, top by confidence:

A	B	Type	Score
RNF125	UBE2E2	psi-mi:“MI:0915”(physical association)	0.670
UBE2E2	RNF125	psi-mi:“MI:0915”(physical association)	0.670
RIGI	NPLOC4	psi-mi:“MI:0915”(physical association)	0.620
RNF125	RIGI	psi-mi:“MI:0915”(physical association)	0.590
VCP	RNF125	psi-mi:“MI:0407”(direct interaction)	0.590
RNF125	RIGI	psi-mi:“MI:0407”(direct interaction)	0.590
RNF125	RIGI	psi-mi:“MI:0914”(association)	0.590
RIGI	RNF125	psi-mi:“MI:0915”(physical association)	0.580
RNF125	RIGI	psi-mi:“MI:0915”(physical association)	0.580
RNF125	RIGI	psi-mi:“MI:0914”(association)	0.580
RNF125	UBE2L3	psi-mi:“MI:0915”(physical association)	0.490
RNF125	UBE2L6	psi-mi:“MI:0915”(physical association)	0.490
RNF125	MAVS	psi-mi:“MI:0915”(physical association)	0.400
RNF125	IFIH1	psi-mi:“MI:0915”(physical association)	0.400
RNF125		psi-mi:“MI:0915”(physical association)	0.370
	RNF125	psi-mi:“MI:0915”(physical association)	0.370
UBE2K	RNF125	psi-mi:“MI:0915”(physical association)	0.370
RNF125	HIP2	psi-mi:“MI:0915”(physical association)	0.370
RNF125	UBE2D1	psi-mi:“MI:0915”(physical association)	0.370
RNF125	UBE2D2	psi-mi:“MI:0915”(physical association)	0.370
RNF125	UBE2D4	psi-mi:“MI:0915”(physical association)	0.370
UBE2D3	RNF125	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (102): RNF125 (Reconstituted Complex), RNF125 (Biochemical Activity), JAK1 (Affinity Capture-Western), RNF125 (Affinity Capture-Western), RNF125 (Affinity Capture-Western), TP53 (Affinity Capture-Western), TP53 (Reconstituted Complex), RNF125 (Affinity Capture-MS), TRIM14 (Affinity Capture-Western), TRIM14 (Biochemical Activity), RNF125 (Biochemical Activity), UBE2D1 (Reconstituted Complex), IL1RL2 (Co-localization), IL1RL2 (Affinity Capture-Western), RNF125 (Synthetic Lethality)

ESM2 similar proteins: F1RB95, O00463, P0C8K8, P61092, P70191, Q06985, Q08CH8, Q15326, Q1L721, Q29RQ5, Q2TAD9, Q3KPU8, Q3MV19, Q3U9F6, Q4R5T4, Q4U5R4, Q5BKL8, Q5FWL3, Q5R7T5, Q6GNX1, Q6IWL4, Q6J1I7, Q6J1I8, Q6J212, Q6J2U6, Q7ZVG6, Q7ZW16, Q84RR0, Q8BH75, Q8GYH7, Q8IUQ4, Q8R5C8, Q8T3Y0, Q920M9, Q94BN0, Q95KF1, Q95M71, Q95M72, Q96A37, Q96EQ8

Diamond homologs: A0JN74, A0JPQ4, A6NLI5, A7E320, B1H278, B2RYR0, D3YY23, O19085, O54952, O60106, O64425, P10862, P15918, P33288, P38398, P48754, Q02084, Q02398, Q03605, Q0IIM1, Q14258, Q17RB8, Q1L5Z9, Q1XH17, Q1XH18, Q28DL4, Q28H21, Q2KHN1, Q2TBT8, Q2YDF9, Q3MV19, Q496Y0, Q4QR06, Q4WZJ6, Q503I2, Q5E9G4, Q5RBG2, Q61510, Q680I0, Q6CTZ8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF125	ubiquitination
RNF125	“down-regulates quantity by destabilization”	IFIH1	polyubiquitination
RNF125	“down-regulates quantity by destabilization”	DDX58	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
Negative regulators of DDX58/IFIH1 signaling	8	145.0×	2e-14
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	102.3×	3e-08
Ovarian tumor domain proteases	5	77.4×	1e-07
E3 ubiquitin ligases ubiquitinate target proteins	6	64.5×	1e-08
Antigen processing: Ubiquitination & Proteasome degradation	11	22.7×	8e-12
Neddylation	5	13.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	5	98.0×	7e-08
protein polyubiquitination	10	57.7×	6e-14
antiviral innate immune response	5	56.9×	7e-07
protein K48-linked ubiquitination	6	50.6×	7e-08
ubiquitin-dependent protein catabolic process	10	37.1×	3e-12
proteasome-mediated ubiquitin-dependent protein catabolic process	8	20.9×	7e-08
protein ubiquitination	6	12.4×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	55
Likely benign	10
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
183420	NM_017831.4(RNF125):c.336G>A (p.Met112Ile)	Pathogenic
3337523	NM_017831.4(RNF125):c.458T>G (p.Leu153Trp)	Likely pathogenic

SpliceAI

846 predictions. Top by Δscore:

Variant	Effect	Δscore
18:32019026:GT:G	donor_gain	1.0000
18:32019028:G:GG	donor_gain	1.0000
18:32042174:TGTA:T	acceptor_loss	1.0000
18:32042177:A:AG	acceptor_gain	1.0000
18:32042177:A:T	acceptor_loss	1.0000
18:32042178:G:GG	acceptor_gain	1.0000
18:32042269:GCAAG:G	donor_gain	1.0000
18:32042270:CAAG:C	donor_loss	1.0000
18:32042271:AAGGT:A	donor_loss	1.0000
18:32042273:GGTT:G	donor_loss	1.0000
18:32042274:G:GA	donor_loss	1.0000
18:32042275:T:A	donor_loss	1.0000
18:32045630:T:TA	acceptor_gain	1.0000
18:32045634:A:AG	acceptor_gain	1.0000
18:32045635:T:G	acceptor_gain	1.0000
18:32045637:TCCA:T	acceptor_loss	1.0000
18:32045640:AG:A	acceptor_gain	1.0000
18:32045641:G:A	acceptor_loss	1.0000
18:32045641:GG:G	acceptor_gain	1.0000
18:32045641:GGT:G	acceptor_gain	1.0000
18:32045641:GGTGT:G	acceptor_gain	1.0000
18:32045730:GTG:G	donor_gain	1.0000
18:32045731:TG:T	donor_gain	1.0000
18:32045731:TGGTA:T	donor_loss	1.0000
18:32045732:GG:G	donor_gain	1.0000
18:32045732:GGT:G	donor_loss	1.0000
18:32045733:G:GG	donor_gain	1.0000
18:32045733:GT:G	donor_loss	1.0000
18:32045734:T:G	donor_loss	1.0000
18:32065900:A:AG	acceptor_gain	1.0000

AlphaMissense

1519 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:32037117:T:C	F56L	0.998
18:32037119:C:A	F56L	0.998
18:32037119:C:G	F56L	0.998
18:32018981:T:C	C40R	0.996
18:32037129:T:C	C60R	0.995
18:32037165:T:C	C72R	0.995
18:32018981:T:A	C40S	0.994
18:32018982:G:C	C40S	0.994
18:32037120:T:C	C57R	0.994
18:32037129:T:A	C60S	0.994
18:32037130:G:A	C60Y	0.994
18:32037130:G:C	C60S	0.994
18:32037131:T:G	C60W	0.994
18:32018972:T:C	C37R	0.993
18:32018983:C:G	C40W	0.993
18:32018974:C:G	C37W	0.992
18:32018982:G:A	C40Y	0.992
18:32019017:T:C	C52R	0.992
18:32037118:T:C	F56S	0.992
18:32037121:G:A	C57Y	0.992
18:32037122:C:G	C57W	0.992
18:32018973:G:A	C37Y	0.991
18:32019025:C:A	H54Q	0.991
18:32019025:C:G	H54Q	0.991
18:32037118:T:G	F56C	0.991
18:32019003:C:A	P47H	0.990
18:32019017:T:A	C52S	0.990
18:32019018:G:C	C52S	0.990
18:32037130:G:T	C60F	0.990
18:32037167:T:G	C72W	0.990

dbSNP variants (sampled 300 via entrez): RS1000030280 (18:32032502 T>G), RS1000088409 (18:32087089 G>C), RS1000139485 (18:32082839 T>C,G), RS1000176891 (18:32049050 C>A,G), RS1000189652 (18:32067677 C>T), RS1000209701 (18:32057526 A>G), RS1000239146 (18:32057323 C>A), RS1000330273 (18:32025713 G>A), RS1000333911 (18:32019459 A>G), RS1000360679 (18:32055329 A>G), RS1000374843 (18:32061944 T>G), RS1000382385 (18:32080375 C>T), RS1000498099 (18:32039165 C>A,G), RS1000527312 (18:32081031 C>G,T), RS1000627535 (18:32045286 C>T)

Disease associations

OMIM: gene MIM:610432 | disease phenotypes: MIM:616260

GenCC curated gene-disease

Disease	Classification	Inheritance
Tenorio syndrome	Strong	Autosomal dominant

Mondo (2): Tenorio syndrome (MONDO:0014553), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (1): Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000270	Delayed cranial suture closure
HP:0000303	Mandibular prognathia
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000506	Telecanthus
HP:0000574	Thick eyebrow
HP:0000712	Emotional lability
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000805	Enuresis
HP:0000938	Osteopenia
HP:0000998	Hypertrichosis
HP:0001097	Keratoconjunctivitis sicca
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001382	Joint hypermobility
HP:0001528	Hemihypertrophy
HP:0001943	Hypoglycemia
HP:0002003	Large forehead
HP:0002020	Gastroesophageal reflux

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation	3
Estradiol	increases expression, decreases expression, affects cotreatment	3
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	decreases expression, increases methylation	2
mercuric bromide	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression, affects response to substance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression, affects expression	2
Cyclosporine	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methyleugenol	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	increases expression	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, decreases expression, affects response to substance	1
gadodiamide	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	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Rosiglitazone	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Methyl Methanesulfonate	decreases expression	1
Progesterone	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9QQ	Ubigene HEK293 RNF125 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy
NCT04426578	PHASE2	UNKNOWN	Role of Perhexiline in Hypertrophic Cardiomyopathy