RNF123

Summary

RNF123 (ring finger protein 123, HGNC:21148) is a protein-coding gene on chromosome 3p21.31, encoding E3 ubiquitin-protein ligase RNF123 (Q5XPI4). Catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase. It is a selective cancer dependency (DepMap: 10.3% of cell lines).

The protein encoded by this gene contains a C-terminal RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions, and an N-terminal SPRY domain. This protein displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor 1B which is also known as p27 or KIP1. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 63891 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 224 total
• Phenotypes (HPO): 1
• Cancer dependency (DepMap): dependent in 10.3% of screened cell lines
• MANE Select transcript: NM_022064

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21148
Approved symbol	RNF123
Name	ring finger protein 123
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12565, KPC1
Ensembl gene	ENSG00000164068
Ensembl biotype	protein_coding
OMIM	614472
Entrez	63891

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 28 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000327697, ENST00000432042, ENST00000433785, ENST00000443204, ENST00000444689, ENST00000454491, ENST00000457726, ENST00000469978, ENST00000486102, ENST00000487805, ENST00000494005, ENST00000497099, ENST00000498376, ENST00000629802, ENST00000859347, ENST00000859348, ENST00000859349, ENST00000859350, ENST00000859351, ENST00000859352, ENST00000859353, ENST00000859354, ENST00000859355, ENST00000859356, ENST00000859357, ENST00000931174, ENST00000931175, ENST00000955447, ENST00000955448, ENST00000955449, ENST00000955450, ENST00000955451, ENST00000955452, ENST00000955453, ENST00000955454, ENST00000955455, ENST00000955456

RefSeq mRNA: 1 — MANE Select: NM_022064 NM_022064

CCDS: CCDS33758

Canonical transcript exons

ENST00000327697 — 39 exons

Exon	Start	End
ENSE00001241098	49704984	49705182
ENSE00001620651	49689557	49689606
ENSE00003474301	49716102	49716177
ENSE00003485668	49691130	49691247
ENSE00003494671	49714090	49714174
ENSE00003505899	49712479	49712656
ENSE00003507760	49706791	49706898
ENSE00003511094	49703427	49703528
ENSE00003511219	49721185	49721529
ENSE00003511512	49698052	49698137
ENSE00003521107	49702334	49702405
ENSE00003526109	49720511	49720653
ENSE00003529420	49697363	49697457
ENSE00003535316	49698755	49698822
ENSE00003542085	49715575	49715714
ENSE00003556005	49705982	49706065
ENSE00003561507	49701811	49701910
ENSE00003561602	49720800	49720894
ENSE00003562474	49721020	49721105
ENSE00003565399	49699668	49699772
ENSE00003587164	49713910	49713997
ENSE00003587884	49704650	49704756
ENSE00003589653	49699468	49699582
ENSE00003592299	49691425	49691509
ENSE00003598799	49705534	49705679
ENSE00003611031	49713513	49713587
ENSE00003619450	49700472	49700564
ENSE00003627391	49697885	49697939
ENSE00003633079	49702083	49702144
ENSE00003640842	49700636	49700709
ENSE00003642402	49716393	49716477
ENSE00003644001	49713738	49713825
ENSE00003646993	49698440	49698526
ENSE00003650926	49701491	49701608
ENSE00003662172	49702633	49702753
ENSE00003675681	49698980	49699105
ENSE00003687508	49715822	49716010
ENSE00003687796	49700227	49700352
ENSE00003690760	49697143	49697222

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5503 / max 118.9985, expressed in 1802 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36658	8.1844	1799
36655	0.2494	60
36657	0.0586	19
36656	0.0580	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	97.66	gold quality
gastrocnemius	UBERON:0001388	96.98	gold quality
vastus lateralis	UBERON:0001379	96.08	gold quality
muscle of leg	UBERON:0001383	96.02	gold quality
muscle organ	UBERON:0001630	95.86	gold quality
quadriceps femoris	UBERON:0001377	95.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.48	gold quality
skeletal muscle tissue	UBERON:0001134	95.24	gold quality
right lobe of liver	UBERON:0001114	94.54	gold quality
triceps brachii	UBERON:0001509	94.43	gold quality
body of tongue	UBERON:0011876	93.93	gold quality
biceps brachii	UBERON:0001507	93.73	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.57	gold quality
diaphragm	UBERON:0001103	93.03	silver quality
gluteal muscle	UBERON:0002000	92.77	gold quality
deltoid	UBERON:0001476	92.65	gold quality
right frontal lobe	UBERON:0002810	92.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.29	gold quality
apex of heart	UBERON:0002098	92.27	gold quality
muscle tissue	UBERON:0002385	92.27	gold quality
cerebellar hemisphere	UBERON:0002245	92.05	gold quality
cerebellar cortex	UBERON:0002129	92.03	gold quality
liver	UBERON:0002107	91.03	gold quality
cerebellum	UBERON:0002037	90.97	gold quality
tibialis anterior	UBERON:0001385	90.67	silver quality
tongue	UBERON:0001723	90.58	gold quality
prefrontal cortex	UBERON:0000451	90.57	gold quality
anterior cingulate cortex	UBERON:0009835	90.28	gold quality
cingulate cortex	UBERON:0003027	90.23	gold quality
caudate nucleus	UBERON:0001873	89.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3, NFE2L2, NRF1, TP53, ZNF699

miRNA regulators (miRDB)

24 targeting RNF123, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-663B	97.40	62.91	664
HSA-MIR-1224-3P	97.24	65.92	851
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-6775-3P	95.76	65.91	982
HSA-MIR-4769-5P	95.37	66.09	570
HSA-MIR-3679-5P	94.75	66.46	862
HSA-MIR-1296-5P	93.94	67.71	305

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• KPC thus probably controls degradation of p27(Kip1) in G1 phase after export of the latter from the nucleus (PMID:15531880)
• Free p27 is recognized by the amino-terminal region of KPC1, which also associates with KPC2, and p27 is then polyubiquitylated by the carboxy-terminal RING-finger domain of KPC1. (PMID:15746103)
• Dendritic cell apoptosis was at least regulated by miR-221 and miR-155 through targeting the 3’-UTRs of p27kip1 and Kip1 ubiquitination-promoting complex 1 (KPC1), respectively. (PMID:21355095)
• This study deministrated that genome-wide significant quantitative trait locus was localized on chromsome 4p15 exhibiting pleiotropic effects on both the endophenotype (lymphocyte-derived expression levels of the RNF123 gene) and disease risk. (PMID:21982424)
• The number of patients with moyamoya disease, which is estimated at approximately one per 300 carriers of RNF123 polymorphism p.R4810K, is considered to be 53,800 in East Asian populations. (PMID:22688066)
• Our data support a role for RNF123 ubiquitin ligase in the degradation of HP1alpha and HP1beta upon lamin A/C knock-down (PMID:23077635)
• up-regulation of RNF123 was restricted to the cingulate cortex of patients with psychotic manifestations of the depression, supporting the role of the ubiquitin system in psychosis. (PMID:23668904)
• Study identified KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. (PMID:25860612)
• Suggest that RNF213 R4810K carriers have lower angiogenic capacities, indicating that they might be more susceptible to insults of cerebral hypoxia. (PMID:26126547)
• RNF123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG-I and MDA5, a function that does not depend on its E3 ligase activity. (PMID:27312109)
• Findings indicate epigenetic regulation of E3 ubiquitin ligase KPC1 associated with NF-kappa B (NF-kappaB) pathway activation, promoting metastatic melanoma progression. (PMID:28389511)
• p27 and its cognate ubiquitin ligases, Skp2/KPC/Pirh2, are specifically involved in determining the clinical profiles of lung carcinomas. (PMID:28601655)
• E3 ubiquitin ligase RNF123 targets LMNB1, Rb protein and LAP2alpha for proteasomal degradation. (PMID:29676528)
• Excess of the NF-kB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1- and chemokines-mediated mechanisms. (PMID:33168738)
• Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain. (PMID:33926923)
• A short binding site in the KPC1 ubiquitin ligase mediates processing of NF-kappaB1 p105 to p50: A potential for a tumor-suppressive PROTAC. (PMID:34873064)
• The Tumor Suppressor Functions of Ubiquitin Ligase KPC1: From Cell-Cycle Control to NF-kappaB Regulator. (PMID:36880841)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf123	ENSDARG00000031269
mus_musculus	Rnf123	ENSMUSG00000041528
rattus_norvegicus	Rnf123	ENSRNOG00000033378
drosophila_melanogaster	Kpc1	FBGN0038296

Paralogs (1): RSPRY1 (ENSG00000159579)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF123 — Q5XPI4 (reviewed: Q5XPI4)

Alternative names: Kip1 ubiquitination-promoting complex protein 1, RING finger protein 123

All UniProt accessions (7): C9J266, C9JI97, C9JN91, C9JS59, Q5XPI4, F8WB91, H7C3U1

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase. Promotes the ubiquitination and proteasome-mediated degradation of CDKN1B which is the cyclin-dependent kinase inhibitor at the G0-G1 transition of the cell cycle. Also acts as a key regulator of the NF-kappa-B signaling by promoting maturation of the NFKB1 component of NF-kappa-B: acts by catalyzing ubiquitination of the NFKB1 p105 precursor, leading to limited proteasomal degradation of NFKB1 p105 and generation of the active NFKB1 p50 subunit. Also functions as an inhibitor of innate antiviral signaling mediated by RIGI and IFIH1 independently of its E3 ligase activity. Interacts with the N-terminal CARD domains of RIGI and IFIH1 and competes with the downstream adapter MAVS.

Subunit / interactions. Component of the KPC complex composed of RNF123/KPC1 and UBAC1/KPC2. Interacts with UBAC1 and CDKN1B via its N-terminal domain. Interacts with RIGI (via N-terminus) and IFIH1 (via N-terminus).

Subcellular location. Cytoplasm.

Post-translational modifications. Ubiquitinated, leading to its degradation. Deubiquitinated by USP19, thereby stimulating CDKN1B ubiquitin-dependent degradation.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. RNF123-mediated maturation of NFKB1 restricts tumor growth by promoting activation of the NF-kappa-B complex, leading to expression of tumor suppressor genes. Activation of NF-kappa-B promotes tumor suppression via CD274/PD-L1 and chemokines-mediated mechanisms.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5XPI4-1	1	yes
Q5XPI4-2	2

RefSeq proteins (1): NP_071347* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR035773	SPRY_RNF123	Domain
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR045129	RNF123/RKP/RSPRY1	Family
IPR057987	TPR_RNF123/RKP	Domain

Pfam: PF00622, PF13920, PF25576

UniProt features (33 total): binding site 8, strand 5, sequence variant 4, modified residue 3, turn 3, mutagenesis site 2, initiator methionine 1, chain 1, splice variant 1, domain 1, sequence conflict 1, zinc finger region 1, helix 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2MA6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5XPI4-F1	81.76	0.45

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 (8): 1277; 1288; 1291; 1254; 1257; 1269; 1271; 1274

Post-translational modifications (3): 2, 675, 683

Mutagenesis-validated functional residues (2):

Position	Phenotype
968–974	abolished ability to bind and ubiquitinate nfkb1.
1256	abolished e3 ubiquitin-protein ligase activity and ability to promote maturation of the nfkb1 component of nf-kappa-b.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 156 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GNF2_ANK1, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_CELL_CYCLE, GNF2_SPTA1, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, GATA1_04, AGCATTA_MIR155, GOBP_PROTEIN_CATABOLIC_PROCESS, PARENT_MTOR_SIGNALING_UP

GO Biological Process (7): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), obsolete proteolysis involved in protein catabolic process (GO:0051603), protein maturation (GO:0051604), canonical NF-kappaB signal transduction (GO:0007249), protein ubiquitination (GO:0016567), protein catabolic process (GO:0030163)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), 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 (3): cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear membrane (GO:0031965)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Deubiquitination	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Post-translational protein modification	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
protein metabolic process	2
cellular anatomical structure	2
modification-dependent protein catabolic process	1
gene expression	1
intracellular signaling cassette	1
protein modification by small protein conjugation	1
macromolecule catabolic process	1
ubiquitin-like protein transferase activity	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
cytoplasm	1
nucleus	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

2496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF123	UBAC1	Q9BSL1	993
RNF123	USP19	O94966	894
RNF123	IP6K1	Q92551	542
RNF123	CDHR4	A6H8M9	522
RNF123	WWP1	Q9H0M0	473
RNF123	SKP2	Q13309	472
RNF123	CUL3	Q13618	460
RNF123	SPATA9	Q9BWV2	453
RNF123	MRPS21	P82921	452
RNF123	CCDC66	A2RUB6	450
RNF123	CDKN1B	P46527	447
RNF123	RCHY1	Q96PM5	446
RNF123	FEM1A	Q9BSK4	440
RNF123	IFIH1	Q9BYX4	437
RNF123	NTRK3	Q16288	434

IntAct

106 interactions, top by confidence:

A	B	Type	Score
UBAC1	RNF123	psi-mi:“MI:0915”(physical association)	0.780
UBAC1	UBB	psi-mi:“MI:0914”(association)	0.740
RNASE3	GGPS1	psi-mi:“MI:0914”(association)	0.640
ELAC2	RNF123	psi-mi:“MI:0914”(association)	0.640
MAP3K6	YWHAG	psi-mi:“MI:0914”(association)	0.640
INSL6	POTEF	psi-mi:“MI:0914”(association)	0.530
AKIRIN2	RGPD3	psi-mi:“MI:0914”(association)	0.530
INSL3	GAPDHS	psi-mi:“MI:0914”(association)	0.530
RDH12	NME2P1	psi-mi:“MI:0914”(association)	0.530
REG4	ATE1	psi-mi:“MI:0914”(association)	0.530
ZNF277	RNF123	psi-mi:“MI:0914”(association)	0.530
GREM2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
PML	NDUFA2	psi-mi:“MI:0914”(association)	0.530
RNF123	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.440
GABARAPL1	RNF123	psi-mi:“MI:0407”(direct interaction)	0.440
RNF123	GABARAPL2	psi-mi:“MI:0407”(direct interaction)	0.440
RNF123	MAP1LC3B	psi-mi:“MI:0407”(direct interaction)	0.440
RNF123	MAP1LC3C	psi-mi:“MI:0407”(direct interaction)	0.440
RNF123	UBE2W	psi-mi:“MI:0915”(physical association)	0.370
ORF6	RNF123	psi-mi:“MI:0915”(physical association)	0.370
RNF123	ENTREP1	psi-mi:“MI:0915”(physical association)	0.370
RNF123	SMAD2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (882): RNF123 (Two-hybrid), RNF123 (Affinity Capture-RNA), RNF123 (Affinity Capture-RNA), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), RNF123 (Affinity Capture-MS)

ESM2 similar proteins: A0A5F9C6I2, A1L3F5, A2BDA5, A3KGS3, A8E4X8, D3ZXK7, F1R7R1, O75129, P21359, P51593, P97526, Q04690, Q1JPG0, Q2PPJ7, Q3SZD5, Q4QQM5, Q4R5A4, Q5RC14, Q5XPI3, Q5XPI4, Q62717, Q66K64, Q6GLR7, Q6NXD8, Q6P4S8, Q6PFH3, Q6VNB8, Q7L4E1, Q7TMY8, Q7Z6Z7, Q80TJ1, Q86UW7, Q8BHR8, Q8BK03, Q8BYR5, Q8CDG3, Q8CF97, Q8CID0, Q8IY22, Q8IZQ1

Diamond homologs: A0A5F9C6I2, A1L252, A2VD92, B0LPN4, D3ZXK7, E9PZQ0, E9Q401, F1LMY4, O94712, P11716, P16960, P21817, P30957, P69566, Q15413, Q19614, Q1LUS8, Q28FM1, Q5R881, Q5XH91, Q5XPI3, Q5XPI4, Q6VN19, Q8BVR6, Q90WU3, Q92736, Q95LP3, Q96DX4, Q96S59, Q9PTY5, Q9VNV3, A1CNW8, A3KMV8, F4HYD7, O74497, P18160, P53076, Q4Z8K6, Q54X16, Q5RBR6

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF123	ubiquitination
RNF123	“down-regulates quantity by destabilization”	CBX1	polyubiquitination
RNF123	“down-regulates quantity by destabilization”	CBX5	polyubiquitination
RNF123	“down-regulates quantity by destabilization”	NFKB1	polyubiquitination
RNF123	“form complex”	KPC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 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
Dengue Virus Genome Translation and Replication	5	18.0×	5e-03
Antigen processing: Ubiquitination & Proteasome degradation	11	4.7×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	5	15.0×	6e-03
mitophagy	5	13.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	187
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

7236 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49691410:T:TA	acceptor_gain	1.0000
3:49697214:A:T	donor_gain	1.0000
3:49697221:GG:G	donor_gain	1.0000
3:49697221:GGGT:G	donor_loss	1.0000
3:49697222:GG:G	donor_gain	1.0000
3:49697223:G:C	donor_loss	1.0000
3:49697223:G:GG	donor_gain	1.0000
3:49697224:T:G	donor_loss	1.0000
3:49697361:A:AG	acceptor_gain	1.0000
3:49697361:AG:A	acceptor_gain	1.0000
3:49697362:G:GT	acceptor_gain	1.0000
3:49697362:GG:G	acceptor_gain	1.0000
3:49697362:GGA:G	acceptor_gain	1.0000
3:49697362:GGAC:G	acceptor_gain	1.0000
3:49697362:GGACA:G	acceptor_gain	1.0000
3:49697454:GGGG:G	donor_gain	1.0000
3:49697455:GGG:G	donor_gain	1.0000
3:49697455:GGGG:G	donor_gain	1.0000
3:49697456:GG:G	donor_gain	1.0000
3:49697456:GGG:G	donor_gain	1.0000
3:49697457:GG:G	donor_gain	1.0000
3:49697458:GTGA:G	donor_loss	1.0000
3:49697460:GAGT:G	donor_loss	1.0000
3:49697938:AGG:A	donor_loss	1.0000
3:49697940:GT:G	donor_loss	1.0000
3:49698134:GGAG:G	donor_gain	1.0000
3:49698135:GAGG:G	donor_gain	1.0000
3:49698435:CCTA:C	acceptor_loss	1.0000
3:49698437:TAGGA:T	acceptor_loss	1.0000
3:49698438:A:C	acceptor_loss	1.0000

AlphaMissense

8552 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49697903:T:A	F121I	1.000
3:49697903:T:C	F121L	1.000
3:49697903:T:G	F121V	1.000
3:49697904:T:C	F121S	1.000
3:49697904:T:G	F121C	1.000
3:49697905:T:A	F121L	1.000
3:49697905:T:G	F121L	1.000
3:49698098:G:C	Q148H	1.000
3:49698098:G:T	Q148H	1.000
3:49698102:G:C	G150R	1.000
3:49698103:G:A	G150D	1.000
3:49698105:T:A	W151R	1.000
3:49698105:T:C	W151R	1.000
3:49698110:C:G	C152W	1.000
3:49698126:T:C	F158L	1.000
3:49698127:T:C	F158S	1.000
3:49698128:C:A	F158L	1.000
3:49698128:C:G	F158L	1.000
3:49698443:G:A	G163R	1.000
3:49698443:G:C	G163R	1.000
3:49698443:G:T	G163W	1.000
3:49698444:G:A	G163E	1.000
3:49698447:T:A	V164D	1.000
3:49698449:G:A	G165R	1.000
3:49698449:G:C	G165R	1.000
3:49698450:G:A	G165E	1.000
3:49698450:G:T	G165V	1.000
3:49698452:G:C	D166H	1.000
3:49698453:A:C	D166A	1.000
3:49698453:A:G	D166G	1.000

dbSNP variants (sampled 300 via entrez): RS1000260554 (3:49709862 C>T), RS1000263343 (3:49704055 C>T), RS1000327602 (3:49697835 G>C), RS1000331247 (3:49697016 C>T), RS1000436098 (3:49704515 G>A,C), RS1000480874 (3:49690120 G>A), RS1000568848 (3:49708558 G>A), RS1000575003 (3:49690407 A>G), RS1000577305 (3:49704264 G>A), RS1000599815 (3:49708268 A>G), RS1000783242 (3:49720182 G>A,C), RS1000848134 (3:49721336 C>T), RS1000902363 (3:49714655 C>G), RS1001232497 (3:49711566 T>G), RS1001326641 (3:49699690 A>C)

Disease associations

OMIM: gene MIM:614472 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hypertrophic cardiomyopathy (MONDO:0005045)

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

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST003795_3	Age at first birth	5.000000e-15
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST005951_49	Body mass index	1.000000e-08
GCST006044_2	Age at first birth	2.000000e-06
GCST006045_5	Age at first birth	6.000000e-10
GCST006920_7	Regular attendance at a gym or sports club	6.000000e-10
GCST006922_9	Regular attendance at a religious group	3.000000e-08
GCST007044_11	Extremely high intelligence	4.000000e-08
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST007565_126	Morning person	3.000000e-18
GCST008512_6	Multisite chronic pain	8.000000e-10
GCST008849_2	Depressive symptoms (binary sum-score)	7.000000e-09
GCST009523_19	Household income	1.000000e-08
GCST009524_240	Household income (MTAG)	1.000000e-14
GCST010002_422	Refractive error	4.000000e-14
GCST010083_229	Hemoglobin levels	6.000000e-12
GCST010083_345	Hemoglobin levels	1.000000e-11
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST90000025_735	Appendicular lean mass	6.000000e-10

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0009101	age at first birth measurement
EFO:0004340	body mass index
EFO:0009592	social interaction measurement
EFO:0004337	intelligence
EFO:0008328	chronotype measurement
EFO:0010100	multisite chronic pain
EFO:0007006	depressive symptom measurement
EFO:0009695	household income
EFO:0004509	hemoglobin measurement
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass

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

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
uranyl acetate	affects expression	1
manganese chloride	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
exemestane	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
(+)-JQ1 compound	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance	1
Methapyrilene	increases methylation	1
Ozone	increases oxidation, increases abundance, affects cotreatment	1
Smoke	decreases expression	1
Uranium	affects expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8UN	Ubigene HCT 116 RNF123 KO	Cancer cell line	Male
CVCL_D9QP	Ubigene HEK293 RNF123 KO	Transformed cell line	Female
CVCL_TJ25	HAP1 RNF123 (-) 1	Cancer cell line	Male
CVCL_TJ26	HAP1 RNF123 (-) 2	Cancer cell line	Male
CVCL_TJ27	HAP1 RNF123 (-) 3	Cancer cell line	Male
CVCL_TJ28	HAP1 RNF123 (-) 4	Cancer cell line	Male
CVCL_TJ29	HAP1 RNF123 (-) 5	Cancer cell line	Male

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