GNL3

Summary

GNL3 (G protein nucleolar 3, HGNC:29931) is a protein-coding gene on chromosome 3p21.1, encoding Guanine nucleotide-binding protein-like 3 (Q9BVP2). May be required to maintain the proliferative capacity of stem cells. It is a common-essential gene (DepMap: required in 96.0% of cancer cell lines).

The protein encoded by this gene may interact with p53 and may be involved in tumorigenesis. The encoded protein also appears to be important for stem cell proliferation. This protein is found in both the nucleus and nucleolus. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 26354 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 109 total
• Cancer dependency (DepMap): dependent in 96.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_014366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29931
Approved symbol	GNL3
Name	G protein nucleolar 3
Location	3p21.1
Locus type	gene with protein product
Status	Approved
Aliases	C77032, E2IG3, MGC800, NS, Nug1
Ensembl gene	ENSG00000163938
Ensembl biotype	protein_coding
OMIM	608011
Entrez	26354

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000394799, ENST00000418458, ENST00000460073, ENST00000462550, ENST00000468146, ENST00000468885, ENST00000474423, ENST00000479230, ENST00000484022, ENST00000492349, ENST00000496254, ENST00000497356, ENST00000858565, ENST00000858566, ENST00000931677, ENST00000931678, ENST00000931679, ENST00000931680

RefSeq mRNA: 3 — MANE Select: NM_014366 NM_014366, NM_206825, NM_206826

CCDS: CCDS2861, CCDS43100

Canonical transcript exons

ENST00000418458 — 15 exons

Exon	Start	End
ENSE00003499092	52693187	52693329
ENSE00003513111	52688109	52688192
ENSE00003524939	52690592	52690704
ENSE00003541317	52693632	52693807
ENSE00003570721	52686769	52686827
ENSE00003573947	52689074	52689206
ENSE00003601281	52694037	52694103
ENSE00003630525	52686032	52686105
ENSE00003631514	52691542	52691629
ENSE00003638370	52687246	52687383
ENSE00003676004	52692872	52693046
ENSE00003681695	52690945	52691071
ENSE00003682703	52687502	52687615
ENSE00003689842	52693408	52693544
ENSE00003845507	52694193	52694497

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 107.1525 / max 1905.7424, expressed in 1819 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36887	103.3837	1817
36885	2.8931	1526
36888	0.3633	129
36889	0.2221	54
36886	0.2163	68
36884	0.0738	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.35	gold quality
body of pancreas	UBERON:0001150	98.31	gold quality
lower esophagus mucosa	UBERON:0035834	98.24	gold quality
pancreas	UBERON:0001264	97.39	gold quality
esophagus mucosa	UBERON:0002469	97.39	gold quality
islet of Langerhans	UBERON:0000006	97.25	gold quality
cartilage tissue	UBERON:0002418	97.14	gold quality
minor salivary gland	UBERON:0001830	97.10	gold quality
rectum	UBERON:0001052	97.05	gold quality
tonsil	UBERON:0002372	96.96	gold quality
adrenal tissue	UBERON:0018303	96.90	gold quality
peritoneum	UBERON:0002358	96.86	gold quality
omental fat pad	UBERON:0010414	96.86	gold quality
skin of abdomen	UBERON:0001416	96.84	gold quality
left ovary	UBERON:0002119	96.82	gold quality
tendon	UBERON:0000043	96.80	gold quality
adenohypophysis	UBERON:0002196	96.71	gold quality
mouth mucosa	UBERON:0003729	96.69	gold quality
right ovary	UBERON:0002118	96.55	gold quality
left uterine tube	UBERON:0001303	96.50	gold quality
pituitary gland	UBERON:0000007	96.49	gold quality
prostate gland	UBERON:0002367	96.39	gold quality
skin of leg	UBERON:0001511	96.33	gold quality
ectocervix	UBERON:0012249	96.32	gold quality
vagina	UBERON:0000996	96.25	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.25	gold quality
body of stomach	UBERON:0001161	96.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.13	gold quality
endocervix	UBERON:0000458	96.03	gold quality
saliva-secreting gland	UBERON:0001044	96.03	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	20.44
E-CURD-112	yes	8.76
E-MTAB-8271	yes	6.63
E-MTAB-6379	no	1306.56
E-MTAB-6911	no	1022.51
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, MYC

miRNA regulators (miRDB)

14 targeting GNL3, 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-548C-3P	99.99	74.01	7587
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-219A-2-3P	98.62	68.78	797
HSA-MIR-6826-5P	93.80	67.42	514

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that nucleostemin can help regulate the proliferation of both cancer cells and stem cells, and may play an important role in the growth regulation of gastric cancer, liver cancer and other cancers. (PMID:15112336)
• nucleostemin has a role in proliferation and tumorigenesis of HeLa cells (PMID:15595646)
• The nucleolar residence of nucleostemin involves a transient and a long-term binding by the basic and GTP-binding domains, and a dissociation mechanism mediated by the COOH-terminal region. (PMID:15657390)
• analysis of nucleolar localization of stem cell protein nucleostemin (PMID:15857956)
• Results implied that nucleostemin may play an important role in both tumorigenesis and transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells. (PMID:16012751)
• Transfected protein interacts with several proteins in COS cells. (PMID:16097049)
• Using a multipotential adherent population of stem cells, nucleostemin was localized to the nucleoli and occurred in 43.3% of the cells. (PMID:16282439)
• Expression widely occurs in normal and malignant renal tissues, and is likely a proliferation marker rather than a unique regulator of cell proliferation and survival in stem and cancer cells. (PMID:16670719)
• In cultured cells, nucleostemin is expressed in a distinct population of epidermal cells from hair follicle kept in the presence of a feeder layer, intimating an association of nucleostemin expression with this type of epithelio-mesenchymal interaction (PMID:17000083)
• Transgenic overexpression of nucleostemin increases the population doubling and decreases the senescence of mouse embryonic fibroblasts. (PMID:17000763)
• A general view of the NS-target genes indicates the possible pathways in which NS plays its role in proliferation control in Hela cells (PMID:17310849)
• These results demonstrate that, in the cells investigated, the level of NS is regulated by p14(ARF) and the control of the G1/S transition by NS operates in a p53-dependent manner. (PMID:17494866)
• may be involved in carcinogenesis of the cervix and progression of cervical carcinoma (PMID:18419830)
• These results suggest that a p53-dependent cell cycle checkpoint monitors changes of cellular NS levels via the impediment of MDM2 function. (PMID:18426907)
• Nucleophosmin is a binding partner of nucleostemin in human osteosarcoma cells (PMID:18448670)
• Nucleostemin expression in cardiomyocytes is induced by fibroblast growth factor-2 and accumulates in response to Pim-1 kinase activity. (PMID:18519946)
• Nucleostemin mRNA and protein are over-expressed in human esophageal squamous cell carcinoma. (PMID:18646696)
• nucleoplasmic relocation of nucleostemin during nucleolar disassembly safeguards the G2-M transit and survival of continuously dividing cells by MDM2 stabilization and p53 inhibition. (PMID:19033382)
• a novel role of nucleostemin in ribosome biogenesis. (PMID:19106111)
• Apoptosis of HL-60 leukemia cells can be induced by silencing NS gene expression. (PMID:19379559)
• Studies demonstrate that NS plays an important role to maintain nucleolar structure and function on a more fundamental level than previously thought. (PMID:19648109)
• data indicate that nucleostemin expression is necessary for cell proliferation and evasion of apoptosis in bladder cancer cells, independent of its effect on p53 (PMID:19706044)
• The upregulation of nucleostemin ,mRNA frequently occurs in ESCC tissues and is associated with malignancy of human esophageal squamous tumors. nucleostemin is required for EGF and EGFR expression. (PMID:19823871)
• NS may promote the progression of prostate cancer by inhibiting the expression of p15, p16, and p18 in PC-3 cells. (PMID:20021940)
• Differential expression of NS, a stem cell marker, and its variants in different types of brain tumor are reported. (PMID:20572164)
• Nucleostemin is an important G1/S checkpoint regulator and it could regulate cell cycles via a p53-independent pathway in prostate cancer. (PMID:20664182)
• Data show that knockdown of NS dramatically reduced the sphere-forming activity of MCF7 and MDA-MB-231 breast cancer cells. (PMID:21045149)
• Reactive oxygen species regulate nucleostemin oligomerization and protein degradation. (PMID:21242306)
• NS is widely expressed in normal and neoplastic oral epithelial tissues, and is likely a marker of proliferation (PMID:21443540)
• Telomere length in Sjogren syndrome is shorter and associated with lower levels of expression of p63 and nucleostemin than in non-Sjogren syndrome. (PMID:21655359)
• a complex composed of TERT, BRG1, and NS/GNL3L maintains the function of tumor initiating cells (PMID:21730156)
• expression in ovarian tumors closely correlated with origination, progression, and grading (PMID:21892090)
• NS inhibits TRF1 dimerization and shortens TRF1 association with the telomere. (PMID:22045740)
• nucleostemin expression level correlated with TWIST expression level in esophageal cancer cell lines; identified that high nucleostemin proportion, TWIST intensity, and advanced pathological N stage were correlated with poor relapse-free survival (PMID:22050045)
• NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation. (PMID:22081066)
• Nucleostemin is expressed in Glioblastoma-cancer stem cells isolated from patient samples, and that its expression, conversely to what it has been described for ordinary stem cells, does not disappear when cells are differentiated. (PMID:22174890)
• NS undergoes a ubiquitin- and MDM2-independent proteasomal degradation when intracellular GTP levels are markedly reduced (PMID:22318725)
• The nucleostemin(NS)could promote the recruitment of PML-IV to SUMOylated TRF1 in TA( ) and ALT cells. (PMID:22641345)
• Nucleostemin can be used for tracking minimal residual disease and is a helpful guide for treatment. (PMID:24119536)
• Data shows that the NS protein expression status was positively correlated with both ER and HER2 status and was a powerful prognostic factor. (PMID:24650343)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnl3	ENSDARG00000006219
mus_musculus	Gnl3	ENSMUSG00000042354
rattus_norvegicus	Gnl3	ENSRNOG00000028461
drosophila_melanogaster	CG10914	FBGN0034307
caenorhabditis_elegans		WBGENE00013001

Paralogs (6): LSG1 (ENSG00000041802), NOA1 (ENSG00000084092), GNL3L (ENSG00000130119), GNL2 (ENSG00000134697), MTG1 (ENSG00000148824), GNL1 (ENSG00000204590)

Protein

Protein identifiers

Guanine nucleotide-binding protein-like 3 — Q9BVP2 (reviewed: Q9BVP2)

Alternative names: E2-induced gene 3 protein, Novel nucleolar protein 47, Nucleolar GTP-binding protein 3, Nucleostemin

All UniProt accessions (4): B4DMU5, C9JYH9, C9JZT7, Q9BVP2

UniProt curated annotations — full annotation on UniProt →

Function. May be required to maintain the proliferative capacity of stem cells. Stabilizes MDM2 by preventing its ubiquitination, and hence proteasomal degradation.

Subunit / interactions. Interacts with MDM2; this interaction stabilizes MDM2. Interaction with MDM2 occurs in the nucleoplasm and is triggered by a nucleolar release mechanism, such as mitosis-induced nucleolar disassembly. Indirectly interacts with TP53, via MDM2-binding. Interacts with TSC22D1 isoform 2.

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Increased levels in lung tissue in cancer patients.

Domain organisation. The basic domain (B) allows nucleolar localization in the absence of GTP. The intermediate domain (I) inhibits nucleolar localization by the B domain and is required for exit from the nucleolus. Exit from the nucleolus to the nucleoplasm requires both the I and the acidic (A) domains, and may be triggered by GTP hydrolysis. In contrast to other GTP-binding proteins, this family is characterized by a circular permutation of the GTPase motifs described by a G4-G1-G3 pattern.

Similarity. Belongs to the TRAFAC class YlqF/YawG GTPase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BVP2-1	1	yes
Q9BVP2-2	2

RefSeq proteins (3): NP_055181, NP_996561, NP_996562 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006073	GTP-bd	Domain
IPR014813	Gnl3_N_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030378	G_CP_dom	Domain
IPR050755	TRAFAC_YlqF/YawG_RiboMat	Family

Pfam: PF01926, PF08701

UniProt features (39 total): cross-link 8, modified residue 6, region of interest 6, compositionally biased region 5, sequence conflict 5, binding site 3, sequence variant 2, chain 1, domain 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
8FKV	ELECTRON MICROSCOPY	2.47
8FKW	ELECTRON MICROSCOPY	2.5
8FL3	ELECTRON MICROSCOPY	2.53
8FKX	ELECTRON MICROSCOPY	2.59
8FKY	ELECTRON MICROSCOPY	2.67
8FL2	ELECTRON MICROSCOPY	2.67
8FKT	ELECTRON MICROSCOPY	2.81
8FKU	ELECTRON MICROSCOPY	2.82
8RL2	ELECTRON MICROSCOPY	2.84
8FKP	ELECTRON MICROSCOPY	2.85
8FKR	ELECTRON MICROSCOPY	2.89
8FL4	ELECTRON MICROSCOPY	2.89
8FL0	ELECTRON MICROSCOPY	2.91
8FKZ	ELECTRON MICROSCOPY	3.04
9QIW	ELECTRON MICROSCOPY	3.04
8INK	ELECTRON MICROSCOPY	3.2
8IPD	ELECTRON MICROSCOPY	3.2
8IPY	ELECTRON MICROSCOPY	3.2
8IR1	ELECTRON MICROSCOPY	3.3
8IR3	ELECTRON MICROSCOPY	3.5
8IPX	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BVP2-F1	75.18	0.42

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 (3): 178–181; 261–268; 305–308

Post-translational modifications (14): 79, 101, 490, 504, 517, 529, 91, 99, 114, 179, 196, 253, 267, 275

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol

MSigDB gene sets: 228 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_PROTEIN_SUMOYLATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_TELOMERE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_STEM_CELL_DIVISION, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_PEPTIDYL_LYSINE_MODIFICATION, MUELLER_PLURINET, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_TELOMERIC_REGION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_PROTEIN_SUMOYLATION, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (7): stem cell division (GO:0017145), stem cell population maintenance (GO:0019827), positive regulation of telomere maintenance (GO:0032206), positive regulation of protein sumoylation (GO:0033235), regulation of cell population proliferation (GO:0042127), positive regulation of miRNA transcription (GO:1902895), positive regulation of protein localization to chromosome, telomeric region (GO:1904816)

GO Molecular Function (5): RNA binding (GO:0003723), GTP binding (GO:0005525), mRNA 5’-UTR binding (GO:0048027), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), chromosome (GO:0005694), nucleolus (GO:0005730), membrane (GO:0016020), nuclear body (GO:0016604), midbody (GO:0030496), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
rRNA processing in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	3
cellular anatomical structure	3
nuclear lumen	2
cell division	1
multicellular organismal process	1
maintenance of cell number	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
protein sumoylation	1
regulation of protein sumoylation	1
positive regulation of protein modification by small protein conjugation or removal	1
cell population proliferation	1
regulation of cellular process	1
positive regulation of DNA-templated transcription	1
miRNA transcription	1
regulation of miRNA transcription	1
positive regulation of miRNA metabolic process	1
protein localization to chromosome, telomeric region	1
positive regulation of protein localization	1
regulation of protein localization to chromosome, telomeric region	1
nucleic acid binding	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
mRNA binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
nucleoplasm	1

Protein interactions and networks

STRING

3633 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNL3	TP53	P04637	954
GNL3	MDM2	Q00987	924
GNL3	SMARCA4	P51532	876
GNL3	GTPBP4	Q9BZE4	725
GNL3	RSL1D1	O76021	716
GNL3	RCC1	P18754	709
GNL3	WDR12	Q9GZL7	696
GNL3	EBNA1BP2	Q99848	661
GNL3	NIFK	Q9BYG3	659
GNL3	DDX56	Q9NY93	615
GNL3	DDX21	Q9NR30	607
GNL3	BOP1	Q14137	600
GNL3	GLT8D1	Q68CQ7	585
GNL3	NPM1	P06748	576
GNL3	NIP7	Q9Y221	571

IntAct

206 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
FBL	NOP56	psi-mi:“MI:0914”(association)	0.800
TERT	SMARCA4	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GNL3	CEP19	psi-mi:“MI:0915”(physical association)	0.660
CEP19	GNL3	psi-mi:“MI:0915”(physical association)	0.660
GNL3	AGO2	psi-mi:“MI:0915”(physical association)	0.640
AGO2	GNL3	psi-mi:“MI:0915”(physical association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
MRPS30	GTPBP10	psi-mi:“MI:0914”(association)	0.640
H1-1	RRP8	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
NP	KPNA6	psi-mi:“MI:0914”(association)	0.550
TERT	GNL3	psi-mi:“MI:0915”(physical association)	0.540
GNL3	TERT	psi-mi:“MI:0403”(colocalization)	0.540
RPS6	IPO7	psi-mi:“MI:0914”(association)	0.530
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RBM34	NVL	psi-mi:“MI:0914”(association)	0.530
STAT3	GNL3	psi-mi:“MI:0915”(physical association)	0.510
GNL3	PPP2R5A	psi-mi:“MI:0915”(physical association)	0.510
PPP2R5A	GNL3	psi-mi:“MI:0915”(physical association)	0.510
TSC22D1	GNL3	psi-mi:“MI:0915”(physical association)	0.500
GNL3	NLE1	psi-mi:“MI:0915”(physical association)	0.500
GNL3	IPO5	psi-mi:“MI:0914”(association)	0.480
ESR1		psi-mi:“MI:0914”(association)	0.460
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460

BioGRID (444): GNL3 (Affinity Capture-MS), GNL3 (Affinity Capture-MS), GNL3 (Affinity Capture-MS), GNL3 (Affinity Capture-MS), GNL3 (Affinity Capture-MS), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation), GNL3 (Co-fractionation)

ESM2 similar proteins: A4IHS0, A5WUX7, A6ZND9, B1P1W2, B3LIY9, B4KPG8, B5XAM2, D2HD32, E7EXT2, O44568, O94443, P25642, P34511, P82673, Q05863, Q08230, Q08DT6, Q08DU1, Q09691, Q12322, Q14197, Q2KI45, Q3T116, Q3UFY8, Q497V5, Q498P2, Q5RDI0, Q5U2R4, Q60R52, Q7JUX9, Q80VP5, Q8C1Z8, Q8K2Y7, Q8MT06, Q8N5C6, Q8R035, Q8VCE1, Q95Q11, Q9BRU9, Q9BVP2

Diamond homologs: A2XGQ1, A4SDB8, A5GR60, A5IMB8, A5N2K5, A5VWQ6, A6LT31, A8EXG4, A8GM60, A8GQS1, A8GUK6, A9KFU3, A9NDV6, B0JFL6, B0KG04, B1JFJ3, B1LBK5, B1X0B0, B2TPB6, B2UX10, B3EGV8, B3PN57, B3QQY9, B3WE42, B4S596, B6J7Q3, B7K1S0, B8GAY7, B8I8N7, B9K8C0, C3PMD9, C4K1B9, J9VQ03, O14236, O67679, O74791, P0CS94, P36915, P36916, P40010

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 220 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
Signaling by ALK in cancer	7	12.0×	1e-04
Nuclear events stimulated by ALK signaling in cancer	5	10.3×	3e-03
MAP kinase activation	5	9.7×	4e-03
Signaling by ALK fusions and activated point mutants	10	9.4×	2e-05
SRP-dependent cotranslational protein targeting to membrane	14	8.8×	5e-07
PTEN Regulation	6	8.6×	2e-03
Response of EIF2AK4 (GCN2) to amino acid deficiency	12	8.4×	6e-06
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	11	8.1×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
ribosomal large subunit biogenesis	8	18.0×	4e-06
positive regulation of miRNA transcription	8	11.8×	8e-05
cytoplasmic translation	12	11.3×	5e-07
translation	18	9.4×	1e-09
negative regulation of translation	9	8.9×	1e-04
rRNA processing	12	8.6×	5e-06
protein import into nucleus	11	8.0×	3e-05
G1/S transition of mitotic cell cycle	7	7.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2494 predictions. Top by Δscore:

Variant	Effect	Δscore
3:52685998:GCAGC:G	donor_gain	1.0000
3:52686001:GC:G	donor_gain	1.0000
3:52686003:G:GG	donor_gain	1.0000
3:52686766:TA:T	acceptor_loss	1.0000
3:52686767:A:AG	acceptor_gain	1.0000
3:52686768:G:GG	acceptor_gain	1.0000
3:52686768:GA:G	acceptor_gain	1.0000
3:52686825:AAGG:A	donor_loss	1.0000
3:52686826:AGG:A	donor_loss	1.0000
3:52686827:GGTA:G	donor_loss	1.0000
3:52686829:T:A	donor_loss	1.0000
3:52687244:A:AG	acceptor_gain	1.0000
3:52687245:G:GG	acceptor_gain	1.0000
3:52687245:GGTTC:G	acceptor_gain	1.0000
3:52687345:G:GT	donor_gain	1.0000
3:52687360:G:T	donor_gain	1.0000
3:52687369:C:G	donor_gain	1.0000
3:52687380:GAGG:G	donor_gain	1.0000
3:52687382:GG:G	donor_gain	1.0000
3:52687383:GG:G	donor_gain	1.0000
3:52687385:T:G	donor_loss	1.0000
3:52687489:AT:A	acceptor_gain	1.0000
3:52687490:T:G	acceptor_gain	1.0000
3:52687490:T:TA	acceptor_gain	1.0000
3:52687491:G:A	acceptor_gain	1.0000
3:52687611:AAAAG:A	donor_loss	1.0000
3:52687612:AAAG:A	donor_loss	1.0000
3:52687614:AGGTA:A	donor_loss	1.0000
3:52687616:G:GA	donor_loss	1.0000
3:52687617:T:G	donor_loss	1.0000

AlphaMissense

3645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:52687250:G:C	R26P	0.992
3:52689201:A:T	K179I	0.992
3:52687262:G:C	R30P	0.991
3:52693322:T:A	W394R	0.991
3:52693322:T:C	W394R	0.991
3:52686789:C:A	R12S	0.990
3:52686808:G:C	R18P	0.990
3:52691560:A:T	K267I	0.986
3:52692918:A:C	S306R	0.986
3:52692920:T:A	S306R	0.986
3:52692920:T:G	S306R	0.986
3:52687344:G:C	K57N	0.985
3:52687344:G:T	K57N	0.985
3:52689117:G:T	R151I	0.985
3:52691562:A:C	S268R	0.984
3:52691564:C:A	S268R	0.984
3:52691564:C:G	S268R	0.984
3:52693248:C:A	A369D	0.983
3:52687256:A:C	H28P	0.982
3:52690621:T:A	W191R	0.981
3:52690621:T:C	W191R	0.981
3:52689118:A:C	R151S	0.977
3:52689118:A:T	R151S	0.977
3:52689136:A:C	R157S	0.977
3:52689136:A:T	R157S	0.977
3:52689123:C:A	P153H	0.976
3:52689135:G:C	R157T	0.975
3:52686817:T:C	I21T	0.974
3:52693302:C:A	A387D	0.974
3:52689202:A:C	K179N	0.973

dbSNP variants (sampled 300 via entrez): RS1000172490 (3:52684145 G>A), RS1000590781 (3:52690344 G>A,C), RS1001115371 (3:52685713 G>A), RS1001766671 (3:52689929 G>A), RS1002056045 (3:52692913 T>C), RS1004621323 (3:52687815 C>A,G,T), RS1004833225 (3:52693913 G>A,C), RS1005015433 (3:52688538 G>T), RS1005285615 (3:52684905 T>C), RS1005763772 (3:52690259 G>A), RS1005852243 (3:52691398 T>G), RS1005864560 (3:52685262 G>A), RS1005918373 (3:52685046 T>C), RS1006297854 (3:52686184 T>C), RS1006351769 (3:52686024 G>A)

Disease associations

OMIM: gene MIM:608011 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001241_15	Bipolar disorder	2.000000e-06
GCST001463_1	Adiponectin levels	2.000000e-13
GCST001465_4	Adiponectin levels	1.000000e-13
GCST001592_2	Osteoarthritis	5.000000e-09
GCST001715_7	Bipolar disorder with mood-incongruent psychosis	2.000000e-06
GCST002149_14	Schizophrenia	1.000000e-08
GCST002539_48	Schizophrenia	4.000000e-11
GCST004521_123	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004521_259	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST004946_141	Schizophrenia	5.000000e-13
GCST005316_130	Intelligence (MTAG)	8.000000e-09
GCST006803_55	Schizophrenia	1.000000e-11
GCST007329_33	Automobile speeding propensity	5.000000e-08
GCST008103_3	Bipolar disorder	7.000000e-11
GCST010698_14	Subcortical volume (min-P)	8.000000e-09
GCST010699_73	Brain morphology (min-P)	1.000000e-18
GCST010701_137	Cortical surface area (MOSTest)	8.000000e-10
GCST010702_70	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_327	Brain morphology (MOSTest)	1.000000e-10
GCST011369_9	Iron status biomarkers (ferritin levels)	4.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0004337	intelligence
EFO:0008579	risk-taking behaviour
EFO:0004346	neuroimaging measurement
EFO:0004459	ferritin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs112242273	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
bisphenol A	decreases expression, decreases methylation	3
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	3
Cyclosporine	increases expression	3
sodium arsenite	decreases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	increases abundance, increases expression, affects expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	decreases expression, increases methylation, affects cotreatment	2
aristolochic acid I	decreases expression	1
OTX015	decreases expression	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
alpha phellandrene	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
deoxynivalenol	increases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
nivalenol	increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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