GSPT1

Summary

GSPT1 (G1 to S phase transition 1, HGNC:4621) is a protein-coding gene on chromosome 16p13.13, encoding Eukaryotic peptide chain release factor GTP-binding subunit ERF3A (P15170). GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA. It is a common-essential gene (DepMap: required in 97.8% of cancer cell lines).

Enables GTPase activity and translation release factor activity. Involved in regulation of translational termination and translational termination. Acts upstream of or within protein methylation. Part of translation release factor complex. Is active in cytosolic ribosome.

Source: NCBI Gene 2935 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 93 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_002094

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4621
Approved symbol	GSPT1
Name	G1 to S phase transition 1
Location	16p13.13
Locus type	gene with protein product
Status	Approved
Aliases	GST1, ETF3A, eRF3a
Ensembl gene	ENSG00000103342
Ensembl biotype	protein_coding
OMIM	139259
Entrez	2935

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 22 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000420576, ENST00000434724, ENST00000439887, ENST00000562169, ENST00000562794, ENST00000563468, ENST00000564790, ENST00000565267, ENST00000567631, ENST00000568849, ENST00000895133, ENST00000895134, ENST00000895135, ENST00000895136, ENST00000895137, ENST00000895138, ENST00000895139, ENST00000895140, ENST00000913280, ENST00000913281, ENST00000913282, ENST00000913283, ENST00000913284, ENST00000945600, ENST00000945601

RefSeq mRNA: 3 — MANE Select: NM_002094 NM_001130006, NM_001130007, NM_002094

CCDS: CCDS45412, CCDS45413, CCDS45414

Canonical transcript exons

ENST00000434724 — 15 exons

Exon	Start	End
ENSE00000829736	11875761	11875929
ENSE00001008692	11915369	11915956
ENSE00001162106	11876086	11876175
ENSE00001162113	11877407	11877580
ENSE00001162132	11886777	11886931
ENSE00001162137	11887570	11887750
ENSE00001162146	11891062	11891139
ENSE00001162155	11894954	11894987
ENSE00001168930	11896558	11896785
ENSE00001757623	11868128	11873171
ENSE00003553868	11897840	11897881
ENSE00003631071	11883015	11883095
ENSE00003664353	11885181	11885274
ENSE00003668123	11897994	11898035
ENSE00003676864	11886471	11886611

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.1680 / max 1716.3355, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156331	36.2914	1822
156332	33.6066	1818
156333	0.4259	195
156334	0.3807	170
156326	0.3790	142
156335	0.0844	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	97.62	gold quality
colonic epithelium	UBERON:0000397	97.57	gold quality
trabecular bone tissue	UBERON:0002483	97.56	gold quality
tongue squamous epithelium	UBERON:0006919	97.28	gold quality
islet of Langerhans	UBERON:0000006	97.09	gold quality
gastrocnemius	UBERON:0001388	97.08	gold quality
ventricular zone	UBERON:0003053	97.04	gold quality
muscle of leg	UBERON:0001383	96.84	gold quality
gingiva	UBERON:0001828	96.65	gold quality
adrenal tissue	UBERON:0018303	96.61	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.59	gold quality
blood	UBERON:0000178	96.55	gold quality
ganglionic eminence	UBERON:0004023	96.52	gold quality
parotid gland	UBERON:0001831	96.46	gold quality
tonsil	UBERON:0002372	96.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.26	gold quality
body of pancreas	UBERON:0001150	96.20	gold quality
rectum	UBERON:0001052	96.19	gold quality
pancreas	UBERON:0001264	96.19	gold quality
cortical plate	UBERON:0005343	96.19	gold quality
bone marrow	UBERON:0002371	96.11	gold quality
monocyte	CL:0000576	96.10	gold quality
bone marrow cell	CL:0002092	96.01	gold quality
muscle organ	UBERON:0001630	95.93	gold quality
right adrenal gland cortex	UBERON:0035827	95.89	gold quality
mononuclear cell	CL:0000842	95.87	gold quality
right adrenal gland	UBERON:0001233	95.87	gold quality
esophagus mucosa	UBERON:0002469	95.76	gold quality
colonic mucosa	UBERON:0000317	95.74	gold quality
stromal cell of endometrium	CL:0002255	95.72	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	40.55
E-MTAB-9221	yes	22.17
E-HCAD-9	yes	6.50
E-MTAB-9467	no	2.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDX2, SP1

miRNA regulators (miRDB)

217 targeting GSPT1, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 29)

• GSPT1/eRF3 is proteolytically processed into an IAP-binding protein (PMID:12865429)
• Human translation termination factor eRF3/GSPT1 is an interacting partner of RNase L. (PMID:15908960)
• Polyglycine expansions in eukaryotic translation release factor 3 are associated with gastric cancer susceptibility (PMID:15987717)
• eRF3a controls the formation of the termination complex by modulating eRF1 protein stability. (PMID:15987998)
• Further, we describe a novel complex that contains the NMD factors SMG-1 and Upf1, and the translation termination release factors eRF1 and eRF3 (SURF). an association between SURF and the EJC is required for SMG-1-mediated Upf1 phosphorylation and NMD. (PMID:16452507)
• These results strongly suggest that the G1 arrest and the decrease in translation induced by eRF3a depletion are due to the inhibition of mTOR activity and hence that eRF3a belongs to the regulatory pathway of mTOR activity. (PMID:17562865)
• GSTP1 inhibits the binding of MAP kinase kinase kinase 5 (MAP3K5) to the 14-3-3 protein, a MAP3K5 inhibitor, while a novel role of GSPT1 is revealed in the regulation of apoptosis signal-regulating kinase 1 (ASK1)-mediated apoptosis. (PMID:17700517)
• eRF3a is degraded by the proteasome when not associated with eRF1; proteasomal degradation of eRF3a controls translation termination complex formation by adjusting the eRF3a level to that of eRF1. (PMID:18083835)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development. (PMID:19424636)
• GSPT1 GGC(12) allele was present in 2.2% of colorectal cancer patients but was absent in Crohn disease patients and in the control group (PMID:19963113)
• crystal structures of the MLLE domain from PABPC1 in complex with the two PAM2 regions of eRF3 (PMID:20418951)
• Our results show that the presence of the longer allele of eRF3a is correlated with threefold increased risk of breast cancer development (PMID:22101789)
• A biological role for the overlapping ERF3 PAM2 motifs in the regulation of deadenylase accessibility to PABPC1 at the 3’ end of poly(A). (PMID:23019593)
• ERF3 is targeted for caspase-mediated proteolytic cleavage and degradation during DNA damage-induced apoptosis. (PMID:23054082)
• The survivin and eRF3 complex may function in spindle formation and segregation of chromosomes and cytokinesis. (PMID:23377885)
• The proteolytic cleavage of eRF3a and eRF3b into p-eRF3 leads to release an amino-terminal fragment containing nuclear export signal to allow the relocalization of eRF3 into the nucleus to interact with the p14ARF. (PMID:24569073)
• Overexpression of ID1 in two different cell lines induced STMN3 and GSPT1 at the transcriptional level, while depletion of ID1 reduced their expression. (PMID:25028095)
• GAB2, GSPT1, TFDP2 and ZFPM1 are four new susceptibility loci for testicular germ cell tumor. (PMID:26503584)
• Data found that the N-terminal glycine repeat of eRF3a influences eRF3a-PABP interaction and that eRF3a 12-GGC allele has a decreased binding affinity for PABP. (PMID:26818177)
• PABP enhances the productive binding of the eRF1-eRF3 complex to the ribosome, via interactions with the N-terminal domain of eRF3a which itself has an active role in translation termination. (PMID:27418677)
• miR-144 was found to be down-regulated in gastric cancer tissues while GSPT1 expression level was markedly increased; GSPT1 was a direct target of miR-144. (PMID:30024602)
• Data show that G1 to S phase transition 1 protein (GSPT1)-rs33635C was a predictor for lamivudine (LAM) therapy. (PMID:30867251)
• miR-27b-3p suppresses gastric cancer cell proliferation, invasion, and migration via negative expression regulation of GSPT1. (PMID:31539861)
• Identification of GSPT1 as prognostic biomarker and promoter of malignant colon cancer cell phenotypes via the GSK-3beta/CyclinD1 pathway. (PMID:33819920)
• Vimentin binds to a novel tumor suppressor protein, GSPT1-238aa, encoded by circGSPT1 with a selective encoding priority to halt autophagy in gastric carcinoma. (PMID:35839920)
• GSPT1 Functions as a Tumor Promoter in Human Liver Cancer. (PMID:36459303)
• MicroRNA-508-3p regulates the proliferation of human lung cancer cells by targeting G1 to S phase transition 1 (GSPT1) protein. (PMID:38099479)
• Potential of GSPT1 as a novel target for glioblastoma therapy. (PMID:39117611)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	gspt1	ENSDARG00000031048
danio_rerio	gspt1l	ENSDARG00000098627
mus_musculus	Gspt1	ENSMUSG00000062203
rattus_norvegicus	Gspt1	ENSRNOG00000046271
drosophila_melanogaster	mEFTu2	FBGN0033184
drosophila_melanogaster	eIF2gamma	FBGN0263740
caenorhabditis_elegans	tufm-2	WBGENE00007001
caenorhabditis_elegans	eif-2gamma	WBGENE00021466

Paralogs (18): MTIF2 (ENSG00000085760), GTPBP1 (ENSG00000100226), EEF1A2 (ENSG00000101210), EFTUD2 (ENSG00000108883), HBS1L (ENSG00000112339), EIF2S3 (ENSG00000130741), EEFSEC (ENSG00000132394), EFL1 (ENSG00000140598), GUF1 (ENSG00000151806), EEF1A1 (ENSG00000156508), EIF5B (ENSG00000158417), GFM2 (ENSG00000164347), EEF2 (ENSG00000167658), GFM1 (ENSG00000168827), GTPBP2 (ENSG00000172432), TUFM (ENSG00000178952), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

Eukaryotic peptide chain release factor GTP-binding subunit ERF3A — P15170 (reviewed: P15170)

Alternative names: G1 to S phase transition protein 1 homolog

All UniProt accessions (4): P15170, H3BMT9, H3BR35, H3BSV8

UniProt curated annotations — full annotation on UniProt →

Function. GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA. GSPT1/ERF3A mediates ETF1/ERF1 delivery to stop codons: The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site. GTP hydrolysis by GSPT1/ERF3A induces a conformational change that leads to its dissociation, permitting ETF1/ERF1 to accommodate fully in the A-site. Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes.

Subunit / interactions. Component of the eRF1-eRF3-GTP ternary complex, composed of ETF1/ERF1 and ERF3 (GSPT1/ERF3A or GSPT2/ERF3B) and GTP. Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. The ETF1-GSPT1 complex interacts with JMJD4. Interacts with PABPC1. Interacts with SHFL.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. ERF3 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P15170-1	1	yes
P15170-2	2
P15170-3	3

RefSeq proteins (3): NP_001123478, NP_001123479, NP_002085* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR004161	EFTu-like_2	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR009001	Transl_elong_EF1A/Init_IF2_C	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031157	G_TR_CS	Conserved_site
IPR050100	TRAFAC_GTPase_members	Family
IPR054696	GTP-eEF1A_C	Domain

Pfam: PF00009, PF03144, PF22594

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (17 total): region of interest 6, binding site 3, sequence conflict 3, splice variant 2, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3KUI	X-RAY DIFFRACTION	2.3
5HXB	X-RAY DIFFRACTION	3.6
6XK9	X-RAY DIFFRACTION	3.64
5LZT	ELECTRON MICROSCOPY	3.65
3E1Y	X-RAY DIFFRACTION	3.8
9HNE	X-RAY DIFFRACTION	3.9
4D61	ELECTRON MICROSCOPY	9
3J5Y	ELECTRON MICROSCOPY	9.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15170-F1	82.08	0.49

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): 220–223; 262–264; 84–89

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-72764	Eukaryotic Translation Termination
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-975956	Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

MSigDB gene sets: 370 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, E2F_Q4, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, HORIUCHI_WTAP_TARGETS_DN, WANG_CLIM2_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GCM_GSPT1, GAANYNYGACNY_UNKNOWN, AAGTCCA_MIR422B_MIR422A, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_16, GGGTGGRR_PAX4_03, GOBP_TRANSLATIONAL_TERMINATION

GO Biological Process (7): G1/S transition of mitotic cell cycle (GO:0000082), nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), translation (GO:0006412), translational termination (GO:0006415), regulation of translational termination (GO:0006449), protein methylation (GO:0006479), ribosome disassembly (GO:0032790)

GO Molecular Function (7): RNA binding (GO:0003723), translation release factor activity (GO:0003747), GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), translation release factor complex (GO:0018444), cytosolic ribosome (GO:0022626)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Nonsense-Mediated Decay (NMD)	2
Translation	1
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational termination	2
cellular anatomical structure	2
cytoplasm	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
nuclear-transcribed mRNA catabolic process	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
protein-containing complex disassembly	1
regulation of translation	1
regulation of protein-containing complex disassembly	1
protein alkylation	1
macromolecule methylation	1
organelle disassembly	1
nucleic acid binding	1
translation termination factor activity	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
protein-containing complex	1
cytosol	1
ribosome	1

Protein interactions and networks

STRING

2279 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSPT1	ETF1	P46055	963
GSPT1	UPF1	Q92900	959
GSPT1	SMG1	Q96Q15	938
GSPT1	SMG9	Q9H0W8	882
GSPT1	CRBN	Q96SW2	878
GSPT1	SMG8	Q8ND04	877
GSPT1	UPF2	Q9HAU5	797
GSPT1	GTPBP4	Q9BZE4	786
GSPT1	UPF3A	Q9H1J1	767
GSPT1	PABPC1	P11940	706
GSPT1	PRKCI	P41743	637
GSPT1	UPF3B	Q9BZI7	609
GSPT1	ZFP91	Q96JP5	597
GSPT1	IKZF3	Q9UKT9	580
GSPT1	CSNK1A1	P48729	572

IntAct

82 interactions, top by confidence:

A	B	Type	Score
ETF1	GSPT1	psi-mi:“MI:0407”(direct interaction)	0.790
ETF1	GSPT1	psi-mi:“MI:0914”(association)	0.790
GSPT1	ETF1	psi-mi:“MI:0915”(physical association)	0.790
BECN1	ZWINT	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LRIF1	SMCHD1	psi-mi:“MI:0914”(association)	0.680
VBP1	PFDN6	psi-mi:“MI:0914”(association)	0.640
UPF1	GSPT1	psi-mi:“MI:0915”(physical association)	0.560
GSPT1	PABPC1	psi-mi:“MI:0915”(physical association)	0.560
GSPT2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
GSPT1	PCNA	psi-mi:“MI:0915”(physical association)	0.370
PIK3R1	GSPT1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
UPF1	GSPT1	psi-mi:“MI:0914”(association)	0.350
ATXN1		psi-mi:“MI:0914”(association)	0.350
GEM	APRT	psi-mi:“MI:0914”(association)	0.350
CHRM4	GEMIN2	psi-mi:“MI:0914”(association)	0.350
ARHGAP23	IPO8	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
rep	ZNF609	psi-mi:“MI:0914”(association)	0.350
TIFAB	DDX3X	psi-mi:“MI:0914”(association)	0.350

BioGRID (389): GSPT1 (Affinity Capture-MS), EEF2 (Co-fractionation), GSPT1 (Co-fractionation), GSPT1 (Co-fractionation), GSPT1 (Co-fractionation), PABPC1 (Co-fractionation), PABPC4 (Co-fractionation), RUVBL1 (Co-fractionation), GSPT1 (Affinity Capture-MS), GSPT1 (Synthetic Lethality), GSPT1 (Affinity Capture-MS), XIAP (Reconstituted Complex), GSPT1 (Affinity Capture-MS), GSPT1 (Affinity Capture-MS), GSPT1 (Proximity Label-MS)

ESM2 similar proteins: O49169, O64937, P02993, P05303, P13549, P15170, P17508, P19039, P25166, P25698, P27592, P29520, P34823, P34824, P40911, P41745, P46198, P46199, P50256, P51554, P53013, P62631, P62632, Q05639, Q08046, Q149F3, Q2HJN4, Q2HJN6, Q2HJN8, Q2HJN9, Q2KHZ2, Q32PH8, Q40034, Q5R4B3, Q5R6Y0, Q5VTE0, Q69ZS7, Q6AXM7, Q71V39, Q7YZN9

Diamond homologs: A0RUM4, A1RXW9, A2BN41, A2Q0Z0, A3DMQ1, A5DPE3, A8ABM5, O13354, O24534, O42820, O49169, O64937, O74718, O93729, P02993, P05453, P06805, P08736, P0CN30, P0CN31, P0CT31, P0CT32, P0CT53, P0CT54, P0CT55, P0CY35, P0DH99, P10126, P13549, P14864, P14865, P14963, P15170, P17507, P17508, P17786, P23637, P25166, P25698, P28295

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GSPT1	“form complex”	“Translation release factor ERF1-ERF3”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2465 predictions. Top by Δscore:

Variant	Effect	Δscore
16:11874316:AT:A	donor_gain	1.0000
16:11875759:AC:A	donor_gain	1.0000
16:11875760:CC:C	donor_gain	1.0000
16:11876084:A:AC	donor_gain	1.0000
16:11876085:C:CC	donor_gain	1.0000
16:11877402:TTTA:T	donor_loss	1.0000
16:11877403:TTA:T	donor_loss	1.0000
16:11877404:TA:T	donor_loss	1.0000
16:11877405:A:AT	donor_loss	1.0000
16:11877406:C:CG	donor_loss	1.0000
16:11877579:TGC:T	acceptor_loss	1.0000
16:11877580:GCTT:G	acceptor_loss	1.0000
16:11877581:C:CC	acceptor_gain	1.0000
16:11877583:T:C	acceptor_gain	1.0000
16:11877583:T:TC	acceptor_gain	1.0000
16:11883101:CAAA:C	acceptor_gain	1.0000
16:11883104:A:AC	acceptor_gain	1.0000
16:11883104:A:C	acceptor_gain	1.0000
16:11885176:GGTA:G	donor_loss	1.0000
16:11885178:TA:T	donor_loss	1.0000
16:11885179:A:C	donor_loss	1.0000
16:11885180:C:A	donor_loss	1.0000
16:11885190:AT:A	donor_gain	1.0000
16:11885191:T:C	donor_gain	1.0000
16:11885270:ATCCA:A	acceptor_gain	1.0000
16:11885271:TCCA:T	acceptor_gain	1.0000
16:11885272:CCA:C	acceptor_gain	1.0000
16:11885272:CCAC:C	acceptor_gain	1.0000
16:11885273:CA:C	acceptor_gain	1.0000
16:11885273:CAC:C	acceptor_gain	1.0000

AlphaMissense

4194 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:11873147:A:T	V491D	1.000
16:11873153:C:A	G489V	1.000
16:11873153:C:T	G489E	1.000
16:11873154:C:G	G489R	1.000
16:11873154:C:T	G489R	1.000
16:11873159:G:T	A487E	1.000
16:11873160:C:G	A487P	1.000
16:11875768:T:A	R480S	1.000
16:11875768:T:G	R480S	1.000
16:11875769:C:A	R480I	1.000
16:11875769:C:G	R480T	1.000
16:11875772:A:G	L479S	1.000
16:11875778:A:G	F477S	1.000
16:11875781:C:G	R476P	1.000
16:11875782:G:T	R476S	1.000
16:11875784:C:A	G475V	1.000
16:11875784:C:T	G475D	1.000
16:11875785:C:G	G475R	1.000
16:11875804:A:C	F468L	1.000
16:11875804:A:T	F468L	1.000
16:11875806:A:G	F468L	1.000
16:11875816:G:C	C464W	1.000
16:11875841:C:G	R456P	1.000
16:11875844:G:T	A455D	1.000
16:11875849:G:C	C453W	1.000
16:11875851:A:G	C453R	1.000
16:11875868:A:T	V447D	1.000
16:11875870:A:C	F446L	1.000
16:11875870:A:T	F446L	1.000
16:11875872:A:G	F446L	1.000

dbSNP variants (sampled 300 via entrez): RS1000010964 (16:11907545 T>C), RS1000027757 (16:11887816 C>A,G,T), RS1000094690 (16:11886304 T>C,G), RS1000114585 (16:11881891 T>A,C), RS1000166899 (16:11881699 G>A,C), RS1000263204 (16:11902787 G>A,C), RS1000327798 (16:11914350 T>C,G), RS1000381537 (16:11913977 G>A,T), RS1000410187 (16:11871966 T>A,C), RS1000431397 (16:11908409 G>A), RS1000489891 (16:11869633 C>T), RS1000498612 (16:11882890 G>A), RS1000673967 (16:11876831 C>T), RS1000752495 (16:11871234 T>C,G), RS1000759514 (16:11875202 G>A)

Disease associations

OMIM: gene MIM:139259 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003246_3	Testicular germ cell tumor	2.000000e-08
GCST005312_36	Menopause (age at onset)	1.000000e-15
GCST008163_149	Height	8.000000e-06
GCST90002386_282	High light scatter reticulocyte percentage of red cells	2.000000e-11
GCST90002403_668	Red blood cell count	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL4296168 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523593 (SINGLE PROTEIN), CHEMBL4523714 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523720 (PROTEIN-PROTEIN INTERACTION), CHEMBL4524003 (PROTEIN-PROTEIN INTERACTION), CHEMBL5169066 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

32 potent at pChembl≥5 of 33 total, top 32 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	EC50	0.1	nM	CHEMBL5094191
9.52	EC50	0.3	nM	CHEMBL4170596
8.05	EC50	9	nM	CHEMBL4742712
7.75	EC50	18	nM	CHEMBL5624834
7.68	EC50	21	nM	CHEMBL5407904
7.54	EC50	29.2	nM	CHEMBL4742712
7.46	EC50	35	nM	CHEMBL5630469
7.32	EC50	48	nM	CHEMBL5631081
7.28	EC50	52	nM	CHEMBL5069911
7.16	EC50	70	nM	CHEMBL5419778
7.07	EC50	86	nM	CHEMBL5630456
7.00	EC50	100	nM	CHEMBL5427975
7.00	EC50	100	nM	CHEMBL4170596
7.00	EC50	100	nM	CHEMBL4742712
6.97	EC50	108	nM	CHEMBL5084741
6.97	EC50	107	nM	CHEMBL4742712
6.84	EC50	143	nM	CHEMBL5629873
6.77	EC50	170	nM	CHEMBL5618808
6.75	EC50	176	nM	CHEMBL5630093
6.68	EC50	208	nM	CHEMBL5629886
6.66	EC50	220	nM	CHEMBL5624867
6.60	EC50	251	nM	CHEMBL5624756
6.35	EC50	447	nM	CHEMBL5624697
6.26	EC50	550	nM	CHEMBL5620230
5.96	EC50	1100	nM	CHEMBL5619824
5.85	EC50	1400	nM	CHEMBL5618377
5.66	EC50	2204	nM	CHEMBL5630649
5.51	EC50	3063	nM	CHEMBL5629972
5.48	EC50	3300	nM	CHEMBL5618646
5.37	EC50	4300	nM	CHEMBL5618970
5.29	EC50	5100	nM	CHEMBL5619492
5.03	EC50	9320	nM	CHEMBL5073414

PubChem BioAssay actives

30 with measured affinity, of 515 total; 28 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2-(trifluoromethoxy)benzenesulfonamide	1814549: PROTAC activity at human CRBN/HiBiT-fused GSPT1 transfected in HEK293T cells assessed as induction of GSPT1 degradation measured after 4 hrs by Nano-Glo HiBiT lytic assay	ec50	0.0001	uM
1-(3-chloro-4-methylphenyl)-3-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]urea	2023110: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 20 hrs by luminescence based assay	ec50	0.0003	uM
2-(4-chlorophenyl)-N-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]-2,2-difluoroacetamide	1709065: Protac activity at CRBN/GSPT1 in human DF15 cells assessed as GSPT1 degradation incubated for 4 hrs by hunter detection reagent based luminescence assay	ec50	0.0090	uM
N-(3-chloro-4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.0180	uM
3-[[(3-chloro-4-methylphenyl)carbamoylamino]methyl]-N-(2,6-dioxopiperidin-3-yl)benzamide	2023110: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 20 hrs by luminescence based assay	ec50	0.0210	uM
N-[3-chloro-5-[[2-methoxyethyl(methyl)amino]methyl]-4-methylphenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.0350	uM
N-[3-chloro-4-methyl-5-(morpholin-4-ylmethyl)phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.0480	uM
N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2-(trifluoromethyl)benzenesulfonamide	1814549: PROTAC activity at human CRBN/HiBiT-fused GSPT1 transfected in HEK293T cells assessed as induction of GSPT1 degradation measured after 4 hrs by Nano-Glo HiBiT lytic assay	ec50	0.0520	uM
1-(3-chloro-4-methylphenyl)-3-[[4-(2,6-dioxopiperidin-3-yl)phenyl]methyl]urea	2023110: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 20 hrs by luminescence based assay	ec50	0.0700	uM
N-[3-chloro-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.0860	uM
4-[[(3-chloro-4-methylphenyl)carbamoylamino]methyl]-N-(2,6-dioxopiperidin-3-yl)benzamide	2023110: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 20 hrs by luminescence based assay	ec50	0.1000	uM
3-chloro-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2-methylbenzenesulfonamide	1814549: PROTAC activity at human CRBN/HiBiT-fused GSPT1 transfected in HEK293T cells assessed as induction of GSPT1 degradation measured after 4 hrs by Nano-Glo HiBiT lytic assay	ec50	0.1080	uM
N-(4-chloro-3-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.1430	uM
2,2,2-trichloroethyl (1S)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	0.1700	uM
N-[3-chloro-4-methyl-5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.1760	uM
N-[3-chloro-4-methyl-5-[(3-morpholin-4-ylazetidin-1-yl)methyl]phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.2080	uM
N-[3-chloro-4-methyl-5-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.2200	uM
N-[3-chloro-4-methyl-5-[[4-(oxan-4-yl)piperazin-1-yl]methyl]phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.2510	uM
N-(3-chloro-4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	0.4470	uM
2,2,2-trichloroethyl (1R)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	0.5500	uM
2,2,2-trichloroethyl (1S)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	1.1000	uM
2,2,2-trichloroethyl (1R)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	1.4000	uM
N-[3-chloro-4-methyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl]-3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propanamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	2.2040	uM
(E)-N-(3-chloro-4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]prop-2-enamide	2134201: PROTAC activity at CRBN/GSPT1 in human U-937 cells assessed as degradation of GSPT1 measured after 6 hrs by Western blot analysis	ec50	3.0630	uM
2,2,2-trichloroethyl (1R)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	3.3000	uM
2,2,2-trichloroethyl (1S)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	4.3000	uM
2,2,2-trichloroethyl (1R)-1-(4-bromophenyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]cycloprop-2-ene-1-carboxylate	2130919: Induction of ePL tagged GSPT1 degradation in human DF15 cells incubated for 60 mins by luminescence reader assay	ec50	5.1000	uM
N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2-methylbenzenesulfonamide	1814549: PROTAC activity at human CRBN/HiBiT-fused GSPT1 transfected in HEK293T cells assessed as induction of GSPT1 degradation measured after 4 hrs by Nano-Glo HiBiT lytic assay	ec50	9.3200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	3
Valproic Acid	affects cotreatment, increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	decreases expression	2
trichostatin A	increases expression	2
sodium arsenite	affects binding, increases reaction, increases expression	2
Formaldehyde	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression	2
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
uranyl acetate	increases expression	1
methylparaben	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
beta-methylcholine	affects expression	1
chloropicrin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
NSC 689534	decreases expression, affects binding	1
Bortezomib	decreases expression	1
Resveratrol	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

267 unique, capped per target: 266 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4219432	Binding	Induction of cereblon-mediated GSPT1 degradation in human DF15 cells expressing ePL-tagged GSPT1 at 0.0005 to 10 uM after 4 hrs by luminometric analysis	A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. — J Med Chem
CHEMBL6181756	Functional	In vivo molecular glue activity at CRBN/GSPT1 in male NOD SCID mouse model xenografted with human LNCaP cells assessed as reduction in GSPT1 level in tumor at 20 mg/kg, po administered daily for 26 days by Western blot analysis	Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders. — J Med Chem

Clinical trials (associated diseases)

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