NOL3

Summary

NOL3 (nucleolar protein 3, HGNC:7869) is a protein-coding gene on chromosome 16q22.1, encoding Nucleolar protein 3 (O60936). May be involved in RNA splicing.

This gene encodes an anti-apoptotic protein that has been shown to down-regulate the enzyme activities of caspase 2, caspase 8 and tumor protein p53. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8996 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myoclonus, familial (Supportive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 72 total
• Phenotypes (HPO): 11
• MANE Select transcript: NM_001276309

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7869
Approved symbol	NOL3
Name	nucleolar protein 3
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	ARC, NOP30, MYP, CARD2
Ensembl gene	ENSG00000140939
Ensembl biotype	protein_coding
OMIM	605235
Entrez	8996

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 35 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000563258, ENST00000563439, ENST00000564053, ENST00000564860, ENST00000564992, ENST00000565560, ENST00000565645, ENST00000566871, ENST00000568086, ENST00000568146, ENST00000568199, ENST00000568503, ENST00000886589, ENST00000886590, ENST00000886591, ENST00000886592, ENST00000886593, ENST00000886594, ENST00000886595, ENST00000886596, ENST00000886597, ENST00000886598, ENST00000886599, ENST00000939545, ENST00000939546, ENST00000939547, ENST00000939548, ENST00000944311, ENST00000944312, ENST00000944313, ENST00000944314, ENST00000944315, ENST00000944316, ENST00000944317, ENST00000944318, ENST00000944319, ENST00000944320, ENST00000944321, ENST00000944322

RefSeq mRNA: 13 — MANE Select: NM_001276309 NM_001185057, NM_001276307, NM_001276309, NM_001276311, NM_001276312, NM_001394973, NM_001394974, NM_001394975, NM_001394976, NM_001394977, NM_001394978, NM_001394979, NM_003946

CCDS: CCDS42176, CCDS58473

Canonical transcript exons

ENST00000564992 — 4 exons

Exon	Start	End
ENSE00002594234	67170538	67170574
ENSE00003606706	67174162	67174464
ENSE00003789753	67174621	67174944
ENSE00003996922	67175047	67175737

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 97.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1773 / max 66.2853, expressed in 1629 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154588	4.4201	1547
154590	2.9838	931
154591	0.5873	320
154592	0.4910	302
154589	0.3860	242
154594	0.1709	75
154593	0.1381	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.78	gold quality
lower esophagus mucosa	UBERON:0035834	97.50	gold quality
gastrocnemius	UBERON:0001388	97.28	gold quality
skin of abdomen	UBERON:0001416	97.20	gold quality
right adrenal gland	UBERON:0001233	97.12	gold quality
right adrenal gland cortex	UBERON:0035827	97.00	gold quality
skin of leg	UBERON:0001511	96.83	gold quality
left adrenal gland	UBERON:0001234	96.68	gold quality
body of pancreas	UBERON:0001150	96.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.66	gold quality
left adrenal gland cortex	UBERON:0035825	96.66	gold quality
right uterine tube	UBERON:0001302	96.55	gold quality
muscle of leg	UBERON:0001383	96.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.52	gold quality
right atrium auricular region	UBERON:0006631	96.49	gold quality
adenohypophysis	UBERON:0002196	96.46	gold quality
minor salivary gland	UBERON:0001830	96.37	gold quality
adrenal cortex	UBERON:0001235	96.33	gold quality
lower esophagus	UBERON:0013473	96.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.32	gold quality
right coronary artery	UBERON:0001625	96.26	gold quality
pituitary gland	UBERON:0000007	96.12	gold quality
mucosa of stomach	UBERON:0001199	95.89	gold quality
heart left ventricle	UBERON:0002084	95.42	gold quality
cardiac ventricle	UBERON:0002082	95.13	gold quality
left coronary artery	UBERON:0001626	95.12	gold quality
cardiac atrium	UBERON:0002081	95.10	gold quality
descending thoracic aorta	UBERON:0002345	95.04	gold quality
saliva-secreting gland	UBERON:0001044	94.94	gold quality
endocervix	UBERON:0000458	94.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	481.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

30 targeting NOL3, 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-656-3P	100.00	72.15	2788
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-934	98.49	70.44	581
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-4433A-5P	96.79	65.01	599
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-9900	96.06	65.48	557
HSA-MIR-4433B-5P	95.91	66.56	727
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-339-3P	94.34	67.96	97

Literature-anchored findings (GeneRIF, showing 31)

• These results suggest that the antiapoptotic effect of apoptotic repressor with caspase recruitment domain is, in part, due to inhibition of voltage-gated potassium channels in cardiomyocytes. (PMID:12734105)
• ARC holds multiple death pathways in check by non-homotypic death-fold interactions. Loss of ARC disinhibits these, leading to accelerated DISC assembly and Bax activation and may be an apoptotic trigger in heart failure and ischemia-reperfusion. (PMID:15383280)
• ARC is recruited to the Fas DISC. By interacting with Fas and FADD through CARD-DD and CARD-DED interactions, ARC prevents DISC assembly and procaspase-8 activation. (PMID:15383280)
• The CARD of ARC binds the Bax C-terminus, preventing Bax activation and activation of the intrinsic mitochondrial pathway (PMID:15383280)
• calcium binding mediates regulation of caspase 8 and cell death by ARC (PMID:15509781)
• Unexpectedly, ARC was localized almost exclusively to the nuclei of cancer cells, which was unlike the cytoplasmic localization of ARC in non-cancer cells (PMID:15848180)
• ARC was present in the cytoplasm and nuclei of epithelial cells in invasive ductal carcinoma (PMID:15861191)
• is downregulated in human failing myocardium (PMID:16505176)
• ARC undergoes poly-ubiquitination and subsequent proteasome-dependent degradation. Mutation of ARC’s lysine residues prevents this and enhances its pro-survival effects. (PMID:17142452)
• nuclear apoptosis repressor with caspase recruitment domain (ARC)is induced in cancer cells and negatively regulates p53 (PMID:18087040)
• the high level of ARC protein and the constitutive phosphorylation of ARC in cancer cells may play an important role in the protection of cancer cells against oxidative stress (PMID:18172857)
• Transfection of cDNA encoding ARC into Me1007 cells inhibited both caspase-8 activation and apoptosis induced by thapsigargin or tunicamycin. (PMID:18245485)
• ARC is a novel marker of human colon cancer and suggest that it may be a general feature of epithelial cancers. (PMID:18469522)
• the balance between antiapoptotic ARC and proapoptotic caspase-8 is the only one to be disturbed during carcinogenesis and tumour progression of renal cell carcinomas (PMID:18516683)
• Ras induces ARC in epithelial cancers, and ARC plays a role in the oncogenic actions of Ras (PMID:20392691)
• Results suggest that ARC expression levels are highly prognostic in AML and that ARC is a potential therapeutic target in AML. (PMID:21041716)
• Data show that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis as well as by promoting chemoresistance in invasive cells. (PMID:22037876)
• ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome. (PMID:22082675)
• HIF-1alpha directly bound to hypoxia-responsive element located at -419 to -414 of ARC gene, which is essential for HIF-1-induced expression. (PMID:22475487)
• This study utilized unbiased, genome-wide approaches to identify a NOL3 mutation that likely causes Familial cortical myoclonus. (PMID:22926851)
• ARC is a previously unrecognized inhibitor of apoptosis in beta-cells and that its protective effects are mediated through suppression of the ER stress response pathway. (PMID:22933109)
• high expression of ARC plays an important role in the pathogenesis of nasopharyngeal carcinoma and leads to X-radiation and cisplatin resistance in nasopharyngeal carcinoma. (PMID:23877130)
• RUNX3, miR-185 and ARC regulate the sensitivity of gastric cancer cells to chemotherapy. (PMID:24763054)
• ARC is regulated via BIRC2/MAP3K14 signalling and its overexpression in AML or MSCs can function as a resistant factor to birinapant-induced leukaemia cell death. (PMID:25079338)
• Results show that in response to DNA damage, p53 total levels increase proportionally to the strength of the damage; however, p53 tetramers are formed at a constant rate under the control of ARC protein. (PMID:25344068)
• Increased ARC expression is associated with liver metastasis of colorectal cancer. (PMID:26721253)
• a novel genetic primary myelofibrosis-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies. (PMID:28232469)
• role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (PMID:28464919)
• Apoptosis repressor with caspase recruitment domain promotes cell proliferation and phenotypic modulation through 14-3-3epsilon/YAP signaling in vascular smooth muscle cells. (PMID:32771410)
• ARC Is a Critical Protector against Inflammatory Bowel Disease (IBD) and IBD-Associated Colorectal Tumorigenesis. (PMID:32816906)
• Expression of apoptosis repressor with caspase recruitment domain (ARC) in familial adenomatous polyposis (FAP) adenomas and its correlation with DNA mismatch repair proteins, p53, Bcl-2, COX-2 and beta-catenin. (PMID:33579312)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nol3	ENSMUSG00000014776
rattus_norvegicus	Nol3	ENSRNOG00000015588

Paralogs (1): CARD6 (ENSG00000132357)

Protein

Protein identifiers

Nucleolar protein 3 — O60936 (reviewed: O60936)

Alternative names: Apoptosis repressor with CARD, Muscle-enriched cytoplasmic protein, Nucleolar protein of 30 kDa

All UniProt accessions (8): O60936, H3BM67, H3BQJ5, H3BUN4, H3BUP2, J3QLS5, J3QLT7, Q5TZN6

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in RNA splicing. Functions as an apoptosis repressor that blocks multiple modes of cell death. Inhibits extrinsic apoptotic pathways through two different ways. Firstly by interacting with FAS and FADD upon FAS activation blocking death-inducing signaling complex (DISC) assembly. Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation. Inhibits intrinsic apoptotic pathway in response to a wide range of stresses, through its interaction with BAX resulting in BAX inactivation, preventing mitochondrial dysfunction and release of pro-apoptotic factors. Inhibits calcium-mediated cell death by functioning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis. Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation. Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner. Also inhibits TNF-induced necrosis by preventing TNF-signaling pathway through TNFRSF1A interaction abrogating the recruitment of RIPK1 to complex I. Finally through its role as apoptosis repressor, promotes vascular remodeling through inhibition of apoptosis and stimulation of proliferation, in response to hypoxia. Inhibits too myoblast differentiation through caspase inhibition.

Subunit / interactions. Oligomerizes (via CARD doamin). Interacts (via CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-dependent manner. Interacts with CASP8; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium. Interacts with TFPT; translocates NOL3 into the nucleus and negatively regulated TFPT-induced cell death. Interacts directly (via CARD domain) with FAS and FADD (via DED domain); inhibits death-inducing signaling complex death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation. Interacts (via CARD domain) with BAX (via a C-terminal 33 residues); inhibits BAX activation and translocation and consequently cytochrome c release from mitochondria. Interacts with PPM1G; may dephosphorylate NOL3. Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the association of BBC3 with BCL2 and resulting in activation of CASP8. Interacts (via CARD domain) with BAD(via BH3 domain); preventing the association of BAD with BCL2. Interacts directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling pathway. Isoform 1 binds to SFRS9/SRp30C.

Subcellular location. Nucleus. Nucleolus Cytoplasm Cytoplasm. Mitochondrion. Sarcoplasmic reticulum. Membrane.

Tissue specificity. Highly expressed in heart and skeletal muscle. Detected at low levels in placenta, liver, kidney and pancreas.

Post-translational modifications. Phosphorylation at Thr-149 is required for its antiapoptotic effect by blocking death-inducing signaling complex death-inducing signaling complex (DISC) activity through the control of interaction with CASP8. Phosphorylation at Thr-149 results in translocation to mitochondria and this translocation enables the binding to CASP8. Dephosphorylated at Thr-149 by calcineurin; doesn’t inhibit the association between FADD and CASP8 and the consequent apoptosis. Polyubiquitinated by MDM2; promoting proteasomal-dependent degradation in response to apoptotic stimuli.

Disease relevance. Myoclonus, familial, 1 (MYOCL1) [MIM:614937] An autosomal dominant neurologic condition characterized by adult onset of cortical myoclonus manifest as involuntary jerks or movements affecting the face and limbs. Affected individuals can also experience falls without seizure activity or loss of consciousness. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. CARD is critical for both extrinsic and intrinsic apoptotic pathways. CARD domain mediates a protective effect against myocardial ischemia/reperfusion, oxidative stress and TNF-induced necrosis. The C-terminal domain (amino acids 99 to 208) is involved in calcium binding and plays a protective role in calcium-mediated cell death.

Induction. Protein expression decreases in hearts failure patients and in response to oxidative stress.

Isoforms (3)

UniProt ID	Names	Canonical?
O60936-2	2, Myp	yes
O60936-1	1, Nop30
O60936-3	3

RefSeq proteins (13): NP_001171986, NP_001263236, NP_001263238, NP_001263240, NP_001263241, NP_001381902, NP_001381903, NP_001381904, NP_001381905, NP_001381906, NP_001381907, NP_001381908, NP_003937 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR052685	Apoptosis_Repressor_CARD	Family

Pfam: PF00619

UniProt features (20 total): helix 5, mutagenesis site 4, sequence variant 2, splice variant 2, initiator methionine 1, chain 1, domain 1, region of interest 1, compositionally biased region 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4UZ0	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60936-F1	72.11	0.37

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 (2): 149, 2

Mutagenesis-validated functional residues (4):

Position	Phenotype
17	abolished ubiquitination in response to an apoptotic stimulus; when associated with r-68 and r-163.
31	did not reduce creatine kinase release or infarct size after myocardial ischemia/reperfusion. causes loss of mitochondri
68	abolished ubiquitination in response to an apoptotic stimulus; when associated with r-17 and r-163.
163	abolished ubiquitination in response to an apoptotic stimulus; when associated with r-17 and r-68.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 482 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GSE45365_NK_CELL_VS_BCELL_UP, MORF_RAGE, GOBP_DENDRITE_DEVELOPMENT, GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, chr16q22, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, MODULE_45, GOBP_DENDRITIC_SPINE_DEVELOPMENT

GO Biological Process (29): response to hypoxia (GO:0001666), blood vessel remodeling (GO:0001974), response to ischemia (GO:0002931), mRNA splice site recognition (GO:0006376), RNA splicing (GO:0008380), regulation of gene expression (GO:0010468), cardiac muscle cell apoptotic process (GO:0010659), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), negative regulation of muscle atrophy (GO:0014736), release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808), response to injury involved in regulation of muscle adaptation (GO:0014876), negative regulation of apoptotic process (GO:0043066), protein complex oligomerization (GO:0051259), negative regulation of programmed necrotic cell death (GO:0062099), negative regulation of release of cytochrome c from mitochondria (GO:0090201), intrinsic apoptotic signaling pathway (GO:0097193), regulation of non-canonical NF-kappaB signal transduction (GO:1901222), negative regulation of mitochondrial membrane permeability involved in apoptotic process (GO:1902109), negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902176), negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway (GO:1903298), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), mRNA processing (GO:0006397), apoptotic process (GO:0006915), negative regulation of signal transduction (GO:0009968), negative regulation of striated muscle cell apoptotic process (GO:0010664), regulation of apoptotic process (GO:0042981), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (10): RNA binding (GO:0003723), death receptor binding (GO:0005123), calcium ion binding (GO:0005509), death effector domain binding (GO:0035877), identical protein binding (GO:0042802), cysteine-type endopeptidase inhibitor activity involved in apoptotic process (GO:0043027), caspase binding (GO:0089720), signaling receptor binding (GO:0005102), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), nucleus (GO:0005634), sarcoplasm (GO:0016528)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
response to stress	2
apoptotic process	2
negative regulation of programmed cell death	2
protein binding	2
intracellular membrane-bounded organelle	2
response to decreased oxygen levels	1
tissue remodeling	1
spliceosomal complex assembly	1
protein-RNA complex assembly	1
RNA processing	1
gene expression	1
regulation of macromolecule biosynthetic process	1
striated muscle cell apoptotic process	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
regulation of muscle atrophy	1
negative regulation of muscle adaptation	1
muscle atrophy	1
sarcoplasmic reticulum calcium ion transport	1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1
response to wounding	1
regulation of apoptotic process	1
protein-containing complex assembly	1
regulation of programmed necrotic cell death	1
programmed necrotic cell death	1
release of cytochrome c from mitochondria	1
negative regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
negative regulation of apoptotic signaling pathway	1
intracellular signal transduction	1
apoptotic signaling pathway	1
non-canonical NF-kappaB signal transduction	1
regulation of intracellular signal transduction	1
negative regulation of mitochondrial membrane permeability	1

Protein interactions and networks

STRING

526 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOL3	CASP8	Q14790	541
NOL3	SRSF9	Q13242	493
NOL3	BFAR	Q9NZS9	413
NOL3	CRADD	P78560	412
NOL3	CASP2	P42575	399
NOL3	KCNJ10	P78508	383
NOL3	FAM98C	Q17RN3	380
NOL3	DAXX	Q9UER7	376
NOL3	DFFA	O00273	361
NOL3	BIRC3	Q13489	351
NOL3	ADAM12	O43184	350
NOL3	BCL2A1	Q16548	340
NOL3	ITGA7	Q13683	339
NOL3	PHAX	Q9H814	337
NOL3	FASTKD3	Q14CZ7	336

IntAct

30 interactions, top by confidence:

A	B	Type	Score
	NOL3	psi-mi:“MI:0915”(physical association)	0.560
NOL3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
NOL3	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
TP53	NOL3	psi-mi:“MI:0915”(physical association)	0.540
TP53	NOL3	psi-mi:“MI:0407”(direct interaction)	0.540
NOL3	CASP8	psi-mi:“MI:0915”(physical association)	0.520
TINF2	NOL3	psi-mi:“MI:0915”(physical association)	0.510
NOL3	NOL3	psi-mi:“MI:0915”(physical association)	0.510
TERF1	NOL3	psi-mi:“MI:0915”(physical association)	0.370
TERF2IP	NOL3	psi-mi:“MI:0915”(physical association)	0.370
NOL3	POT1	psi-mi:“MI:0915”(physical association)	0.370
NOL3	SIRPA	psi-mi:“MI:0915”(physical association)	0.370
VASP	NOL3	psi-mi:“MI:0915”(physical association)	0.370
NOL3	NIF3L1	psi-mi:“MI:0915”(physical association)	0.370
NOL3	ETNK2	psi-mi:“MI:0915”(physical association)	0.370
NRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
PACSIN3	NOL3	psi-mi:“MI:0915”(physical association)	0.000
PNKP	NOL3	psi-mi:“MI:0915”(physical association)	0.000
NOL3	TINF2	psi-mi:“MI:0915”(physical association)	0.000
	NOL3	psi-mi:“MI:0915”(physical association)	0.000
UBQLN2	NOL3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (57): NOL3 (Two-hybrid), NOL3 (Two-hybrid), SIRPA (Two-hybrid), NOL3 (Two-hybrid), NIF3L1 (Two-hybrid), ETNK2 (Two-hybrid), NOL3 (Affinity Capture-Western), NOL3 (Synthetic Lethality), DAXX (Affinity Capture-Western), NOL3 (Affinity Capture-Western), NOL3 (Affinity Capture-MS), NOL3 (Affinity Capture-MS), NOL3 (Affinity Capture-Western), NOL3 (Affinity Capture-Western), NOL3 (Affinity Capture-RNA)

ESM2 similar proteins: A5D7L8, A5PJC7, A6NCS6, D3YXK1, F5GYI3, O00221, O60936, O94989, P0C1Z6, P17564, Q0VG99, Q0X0E2, Q17QH7, Q2KI51, Q2M3G4, Q2TAM9, Q3TVI4, Q3U1J1, Q4KLY2, Q5R866, Q5SV97, Q5VTJ3, Q60465, Q62881, Q62985, Q673H1, Q6PAJ3, Q6PJ61, Q6SPE9, Q6SPF0, Q6ZMQ8, Q6ZNE9, Q7TSX9, Q80SU3, Q80VJ8, Q86SH2, Q86VE0, Q8BG26, Q8BG80, Q8BNN1

Diamond homologs: O60936, Q62881, Q9BX69, Q9D1X0, A0JN92, Q5NCI0, Q5RFJ8, Q8TCY9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CSNK2A2	“up-regulates activity”	NOL3	phosphorylation
CSNK2A1	“up-regulates activity”	NOL3	phosphorylation
UBE3A	“down-regulates quantity by destabilization”	NOL3	ubiquitination
GSK3A	“down-regulates quantity by destabilization”	NOL3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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
DNA Damage/Telomere Stress Induced Senescence	5	58.3×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance	5	170.2×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	19
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

826 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67170633:G:T	donor_gain	1.0000
16:67174157:TGCA:T	acceptor_loss	1.0000
16:67174159:CAG:C	acceptor_loss	1.0000
16:67174160:A:AG	acceptor_gain	1.0000
16:67174160:AGCC:A	acceptor_loss	1.0000
16:67174161:G:GA	acceptor_gain	1.0000
16:67174161:GC:G	acceptor_gain	1.0000
16:67174161:GCC:G	acceptor_gain	1.0000
16:67174161:GCCC:G	acceptor_gain	1.0000
16:67174161:GCCCC:G	acceptor_gain	1.0000
16:67174451:GCAC:G	donor_gain	1.0000
16:67174927:A:T	donor_gain	1.0000
16:67174932:G:T	donor_gain	1.0000
16:67174945:GT:G	donor_gain	1.0000
16:67170570:GACCC:G	donor_gain	0.9900
16:67170575:G:GG	donor_gain	0.9900
16:67170607:G:GT	donor_gain	0.9900
16:67174156:A:AG	acceptor_gain	0.9900
16:67174157:T:G	acceptor_gain	0.9900
16:67174157:T:TA	acceptor_gain	0.9900
16:67174299:GA:G	donor_gain	0.9900
16:67174463:GG:G	donor_gain	0.9900
16:67174464:GG:G	donor_gain	0.9900
16:67174618:CA:C	acceptor_loss	0.9900
16:67174619:A:AG	acceptor_gain	0.9900
16:67174620:G:A	acceptor_loss	0.9900
16:67174620:G:GG	acceptor_gain	0.9900
16:67174926:G:GT	donor_gain	0.9900
16:67174940:CGAAG:C	donor_loss	0.9900
16:67174941:GAAGG:G	donor_loss	0.9900

AlphaMissense

1293 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67174204:T:A	I12N	0.990
16:67174288:T:A	L40H	0.988
16:67174302:T:C	Y45H	0.988
16:67174216:G:C	R16P	0.987
16:67174264:A:T	D32V	0.987
16:67174225:T:C	L19P	0.986
16:67174351:T:C	L61P	0.986
16:67174396:T:C	L76P	0.986
16:67174354:T:A	L62Q	0.983
16:67174354:T:C	L62P	0.982
16:67174261:T:C	L31S	0.981
16:67174270:T:C	L34P	0.981
16:67174263:G:C	D32H	0.980
16:67174344:C:A	R59S	0.980
16:67174270:T:A	L34Q	0.977
16:67174375:G:T	G69V	0.976
16:67174228:T:A	V20D	0.975
16:67174237:T:C	L23P	0.975
16:67174374:G:T	G69C	0.975
16:67174312:T:C	L48S	0.974
16:67174396:T:A	L76Q	0.974
16:67174204:T:G	I12S	0.972
16:67174351:T:A	L61Q	0.972
16:67174374:G:C	G69R	0.972
16:67174264:A:C	D32A	0.970
16:67174303:A:G	Y45C	0.970
16:67174270:T:G	L34R	0.969
16:67174373:G:C	K68N	0.968
16:67174373:G:T	K68N	0.968
16:67174263:G:A	D32N	0.967

dbSNP variants (sampled 300 via entrez): RS1000775480 (16:67169222 C>T), RS1000937270 (16:67175576 TG>T), RS1001482651 (16:67175229 G>A), RS1001624778 (16:67170059 A>T), RS1001641499 (16:67175138 G>A,T), RS1002577583 (16:67173291 T>G), RS1003141036 (16:67171378 T>A,G), RS1003341902 (16:67170201 G>C), RS1003782501 (16:67173698 C>T), RS1004968620 (16:67172839 A>G), RS1005106406 (16:67172367 C>G), RS1005301038 (16:67171348 G>GGAACA), RS1005942408 (16:67175543 G>A), RS1006392011 (16:67176220 C>A), RS1006523855 (16:67170867 G>A,C)

Disease associations

OMIM: gene MIM:605235 | disease phenotypes: MIM:614937

GenCC curated gene-disease

Disease	Classification	Inheritance
myoclonus, familial	Supportive	Autosomal dominant
myoclonus, familial, 1	Limited	Autosomal dominant

Mondo (2): myoclonus, familial, 1 (MONDO:0100093), myoclonus, familial (MONDO:0013981)

Orphanet (1): Familial cortical myoclonus (Orphanet:319189)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001251	Ataxia
HP:0001336	Myoclonus
HP:0002345	Action tremor
HP:0002359	Frequent falls
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0011462	Young adult onset
HP:0034360	Action myoclonus
HP:0100785	Insomnia

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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, increases methylation	3
Estradiol	affects expression, decreases expression	2
Valproic Acid	decreases expression, increases methylation	2
Cyclosporine	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
aminomethylphosphonic acid (AMPA)	increases expression	1
tungsten carbide	affects cotreatment, increases expression	1
beauvericin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
VX-agent	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cypermethrin	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
coumarin	increases phosphorylation	1
mercuric bromide	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
monomethylarsonous acid	decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
brevetoxin 2	increases expression	1

Clinical trials (associated diseases)

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