GPSM2

Summary

GPSM2 (G protein signaling modulator 2, HGNC:29501) is a protein-coding gene on chromosome 1p13.3, encoding G-protein-signaling modulator 2 (P81274). Plays an important role in mitotic spindle pole organization via its interaction with NUMA1.

The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 29899 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Chudley-McCullough syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 306 total — 12 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 16
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_013296

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29501
Approved symbol	GPSM2
Name	G protein signaling modulator 2
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	LGN, Pins
Ensembl gene	ENSG00000121957
Ensembl biotype	protein_coding
OMIM	609245
Entrez	29899

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 28 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000264126, ENST00000406462, ENST00000435475, ENST00000435987, ENST00000441735, ENST00000446797, ENST00000642355, ENST00000643094, ENST00000643643, ENST00000643921, ENST00000645164, ENST00000645255, ENST00000674663, ENST00000674700, ENST00000674731, ENST00000674914, ENST00000675086, ENST00000675087, ENST00000675617, ENST00000675740, ENST00000675776, ENST00000675829, ENST00000676184, ENST00000676404, ENST00000876528, ENST00000876529, ENST00000876530, ENST00000876531, ENST00000876532, ENST00000876533, ENST00000942318, ENST00000942319, ENST00000942320, ENST00000942321, ENST00000942322, ENST00000942323

RefSeq mRNA: 3 — MANE Select: NM_013296 NM_001321038, NM_001321039, NM_013296

CCDS: CCDS792

Canonical transcript exons

ENST00000264126 — 15 exons

Exon	Start	End
ENSE00001024150	108885275	108885578
ENSE00001561061	108929701	108934545
ENSE00001614490	108901790	108901945
ENSE00001621482	108914338	108914408
ENSE00001625275	108918613	108918789
ENSE00001644377	108924000	108924214
ENSE00001672146	108903126	108903234
ENSE00001689752	108898642	108898765
ENSE00001752230	108897492	108897627
ENSE00001754383	108904125	108904254
ENSE00001774460	108898879	108898994
ENSE00001783677	108897959	108898101
ENSE00001792285	108922417	108922576
ENSE00002221677	108896864	108897085
ENSE00003821276	108876985	108877228

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.4866 / max 272.8011, expressed in 1601 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4373	7.5438	1478
4375	4.1464	1032
4374	1.0792	644
4376	0.6377	310
4377	0.0795	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	98.17	gold quality
buccal mucosa cell	CL:0002336	98.05	gold quality
amniotic fluid	UBERON:0000173	96.07	gold quality
tendon of biceps brachii	UBERON:0008188	95.83	gold quality
tendon	UBERON:0000043	95.77	gold quality
ventricular zone	UBERON:0003053	95.63	gold quality
tongue squamous epithelium	UBERON:0006919	95.26	gold quality
endothelial cell	CL:0000115	95.25	gold quality
corpus callosum	UBERON:0002336	95.19	gold quality
esophagus squamous epithelium	UBERON:0006920	95.16	gold quality
calcaneal tendon	UBERON:0003701	94.73	gold quality
medial globus pallidus	UBERON:0002477	94.71	gold quality
inferior vagus X ganglion	UBERON:0005363	94.47	gold quality
squamous epithelium	UBERON:0006914	94.14	gold quality
epithelium of esophagus	UBERON:0001976	94.00	gold quality
body of tongue	UBERON:0011876	93.99	gold quality
pharyngeal mucosa	UBERON:0000355	93.88	gold quality
globus pallidus	UBERON:0001875	93.86	gold quality
gingival epithelium	UBERON:0001949	93.35	gold quality
superior vestibular nucleus	UBERON:0007227	93.11	gold quality
gingiva	UBERON:0001828	93.02	gold quality
medulla oblongata	UBERON:0001896	92.96	gold quality
subthalamic nucleus	UBERON:0001906	92.75	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.75	gold quality
oral cavity	UBERON:0000167	92.18	gold quality
spinal cord	UBERON:0002240	92.18	gold quality
nipple	UBERON:0002030	92.17	gold quality
tongue	UBERON:0001723	92.13	gold quality
ventral tegmental area	UBERON:0002691	92.01	gold quality
penis	UBERON:0000989	91.85	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	488.77
E-ANND-3	yes	10.09
E-GEOD-150728	no	2536.54
E-CURD-46	no	31.03
E-GEOD-137537	no	3.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting GPSM2, 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-3924	100.00	72.09	2394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-22-3P	99.93	68.13	917

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 34)

• LGN is expressed in neuronal, astroglial, and microglial cultures (PMID:11832491)
• binding between Lgl2 and LGN play a role in mitotic spindle organization through regulating formation of the LGN.NuMA complex; Lgl2 forms a Lgl2.Par-6.aPKC.LGN complex, which responds to mitotic signaling to establish normal cell division (PMID:15632202)
• Ric-8A and Gi alpha recruit LGN, NuMA, and dynein to the cell cortex to help orient the mitotic spindle. (PMID:20479129)
• Upregulation of GPSM2 is associated with breast cancer. (PMID:20589935)
• Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss. (PMID:20602914)
• During mitosis, Pins is mislocalized to the apical surface in the absence of Par3 or by inhibition of atypical protein kinase C. (PMID:20933426)
• A novel truncating mutation of GPSM2 is associated with autosomal recessive non-syndromic hearing loss. (PMID:21348867)
• mInsc-LGN interaction is vital for stabilization of LGN and for intracellular localization of mInsc. (PMID:22074847)
• GPSM2 is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development (PMID:22578326)
• Overexpression of LGN decreases the activity of cellular sGC, whereas knockdown of LGN mRNA and protein correlated with increased sGC activity (PMID:22690686)
• Studies indicate that the Inscuteable (Insc)and NuMA are mutually exclusive interactors of LGN. (PMID:22977735)
• Results show compound heterozygous mutations in the GPSM2 gene, in affected members of a family with Chudley-McCullough syndrome, co-segregate in the family as an autosomal recessive trait. (PMID:22987632)
• Data indicate that dynein- and astral microtubule-mediated transport of Galphai/LGN/nuclear mitotic apparatus (NuMA) complex from cell cortex to spindle poles. (PMID:23389635)
• one homozygous frameshift GPSM2 variants c.1473delG was identified in three Chudley-McCullough syndrome Dutch patients. (PMID:23494849)
• LGN is required for mitotic spindle rotation but not orientation maintenance. (PMID:23907121)
• Hepatocyte Par1b defines lumen position in concert with the position of the astral microtubule anchoring complex LGN-NuMA to yield the distinct epithelial division phenotypes. (PMID:24165937)
• A crystal structure of Frmpd4-bound LGN in an oxidized form is also reported, although oxidation does not appear to strongly affect the interaction with Frmpd4. (PMID:25664792)
• results fit a model whereby LGN influences interphase microtubule dynamics in endothelial cells to regulate migration, cell adhesion, and sprout extension, and reveal a novel non-mitotic role for LGN in sprouting angiogenesis (PMID:26398908)
• Kinocilium is essential for proper localization of Lgn, as well as Gai and aPKC, suggesting that cilium function plays a role in positioning of apical proteins critical for hearing. (PMID:26662512)
• This study determined the crystallographic structure of human Afadin in complex with LGN. (PMID:26751642)
• Data support the notion that the Galpha, but not Gbetagamma, arm of the Gi/o signalling is involved in TRPC4 activation and unveil new roles for RGS and LGN in fine-tuning TRPC4 activities. (PMID:26987813)
• A novel mutation (c.1093C > T; p.Arg365*) is described in a family with dizygotic twins with variable phenotype of Chudley-McCullough syndrome. (PMID:27064331)
• This mutation is predicted to abolish all four GoLoco domains in GPSM2 and this explains the bioinformatic prediction for this mutation to be functionally damaging. Full clinical and molecular accounts of the novel mutation are provided in this paper. (PMID:27180139)
• The results show how E-cadherin instructs the assembly of the LGN/NuMA complex at cell-cell contacts, and define a mechanism that couples cell division orientation to intercellular adhesion. (PMID:28045117)
• high expression of G-protein signaling modulator 2 was involved in the pathological processes of hepatocellular carcinoma through activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which may provide an attractive potential diagnostic biomarker and therapeutic target for treatment of hepatocellular carcinoma. (PMID:28347229)
• Endothelial flow mechanotransduction through the junctional complex is mediated by a specific pool of VE-cadherin that is phosphorylated on cytoplasmic tyrosine Y658 and bound to LGN. (PMID:28712573)
• In mammary stem cells, the asymmetric domain of Insc bound to LGN:Galphai(GDP) suffices to drive asymmetric fate, and reverts aberrant symmetric divisions induced by p53 loss. (PMID:29523789)
• Study reports the crystal structure of NuMA:LGN hetero-hexamers, and unveil their role in promoting the assembly of active cortical dynein/dynactin motors that are required in orchestrating oriented divisions in polarized cells. (PMID:31101817)
• LGN has a role in cell cortex recruitment of NuMA (PMID:31732560)
• Downregulation of GPSM2 is associated with primary resistance to paclitaxel in breast cancer. (PMID:32020211)
• Loss of G-protein-signaling modulator 2 accelerates proliferation of lung adenocarcinoma via EGFR signaling pathway. (PMID:32058048)
• GPSM2 Serves as an Independent Prognostic Biomarker for Liver Cancer Survival. (PMID:32812493)
• Truncated isoforms of GPSM2 containing the GoLoco motif region promote CD4(+) T-cell migration in SLE. (PMID:35940821)
• G-Protein Signaling Modulator 2 as a Potential Biomarker in Colorectal Cancer: Integrative Analysis Using Genetic Profiling and Pan-Cancer Studies. (PMID:38674408)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpsm2	ENSDARG00000017311
mus_musculus	Gpsm2	ENSMUSG00000027883
rattus_norvegicus	Gpsm2	ENSRNOG00000012149

Paralogs (6): TTC28 (ENSG00000100154), TTC29 (ENSG00000137473), GPSM1 (ENSG00000160360), RAPSN (ENSG00000165917), TTC24 (ENSG00000187862), GPSM3 (ENSG00000213654)

Protein

Protein identifiers

G-protein-signaling modulator 2 — P81274 (reviewed: P81274)

Alternative names: Mosaic protein LGN

All UniProt accessions (14): A0A2R8Y673, A0A2R8Y6E3, A0A2R8Y896, A0A2R8YCX1, A0A6Q8PF02, A0A6Q8PFD2, A0A6Q8PGS6, A0A6Q8PGU2, A0A6Q8PGW7, B0QZC9, B0QZD0, P81274, H0Y4A4, Q5T1N9

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in mitotic spindle pole organization via its interaction with NUMA1. Required for cortical dynein-dynactin complex recruitment during metaphase. Plays a role in metaphase spindle orientation. Also plays an important role in asymmetric cell divisions. Has guanine nucleotide dissociation inhibitor (GDI) activity towards G(i) alpha proteins, such as GNAI1 and GNAI3, and thereby regulates their activity.

Subunit / interactions. Interacts with the dynein-dynactin complex; this interaction is inhibited in a PLK1-dependent manner. Part of a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1. Interacts with LLGL2. Interacts (via TPR repeat region) with INSC/inscuteable. Interacts (via TPR repeat region) with NUMA1 (via C-terminus); this interaction is direct, inhibited in a PLK1-dependent manner, prevents the binding of NUMA1 with SPAG5 and promotes spindle pole organization. INSC and NUMA1 compete for the same binding site, but INSC has higher affinity and can displace NUMA1 (in vitro). Interacts with GNAI2. Interacts (via GoLoco domains) with the GDP-bound form of GNAI1 and GNAI3; has much lower affinity for the GTP-bound form. Interaction with GDP-bound GNAI3 strongly enhances the affinity for NUMA1. Interacts (via TPR repeat region) with FRMPD1. INSC and FRMPD1 compete for the same binding site, but INSC has higher affinity and can displace FRMPD1 (in vitro). Interacts (via TPR repeat region) with FRMPD4. Identified in a complex with INSC and F2RL2/Par3. Interacts with TASOR.

Subcellular location. Cytoplasm. Cell cortex. Cytoskeleton. Spindle pole. Lateral cell membrane.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Chudley-McCullough syndrome (CMCS) [MIM:604213] An autosomal recessive neurologic disorder characterized by early-onset sensorineural deafness and specific brain anomalies on MRI, including hypoplasia of the corpus callosum, enlarged cysterna magna with mild focal cerebellar dysplasia, and nodular heterotopia. Some patients have hydrocephalus. Psychomotor development is normal. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Dysfunction of LGN is associated with the phenotype of multiple micronuclei due to chromosomal mis-segregation and defect in cell division through mis-localization of mitotic spindle regulator protein NUMA1.

Similarity. Belongs to the GPSM family.

RefSeq proteins (3): NP_001307967, NP_001307968, NP_037428* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003109	GoLoco_motif	Conserved_site
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR052386	GPSM	Family

Pfam: PF02188, PF13176, PF13181, PF13374, PF13424

UniProt features (50 total): helix 18, modified residue 9, repeat 8, domain 4, binding site 4, mutagenesis site 4, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4WND	X-RAY DIFFRACTION	1.5
4WNE	X-RAY DIFFRACTION	2
4WNG	X-RAY DIFFRACTION	2.11
3SF4	X-RAY DIFFRACTION	2.6
4WNF	X-RAY DIFFRACTION	2.9
5A6C	X-RAY DIFFRACTION	2.9
6HC2	X-RAY DIFFRACTION	4.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P81274-F1	66.96	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 608; 613; 642; 647

Post-translational modifications (9): 132, 352, 408, 483, 486, 501, 541, 565, 607

Mutagenesis-validated functional residues (4):

Position	Phenotype
228	abolishes location at mitotic spindle poles; when associated with a-243.
228	strongly reduces interaction with insc. abolishes interaction with insc; when associated with r-290.
243	abolishes location at mitotic spindle poles; when associated with a-228.
290	abolishes interaction with insc; when associated with e-228.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 348 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_SPINDLE_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, PATIL_LIVER_CANCER, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, MODULE_205

GO Biological Process (10): establishment of mitotic spindle orientation (GO:0000132), mitotic spindle organization (GO:0007052), G protein-coupled receptor signaling pathway (GO:0007186), response to light intensity (GO:0009642), cell division (GO:0051301), maintenance of centrosome location (GO:0051661), regulation of mitotic spindle organization (GO:0060236), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), positive regulation of protein localization to cell cortex (GO:1904778), positive regulation of spindle assembly (GO:1905832)

GO Molecular Function (8): nucleotide binding (GO:0000166), G-protein alpha-subunit binding (GO:0001965), GDP-dissociation inhibitor activity (GO:0005092), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), dynein complex binding (GO:0070840), protein binding (GO:0005515), GTPase regulator activity (GO:0030695)

GO Cellular Component (14): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), cell cortex (GO:0005938), postsynaptic density (GO:0014069), lateral plasma membrane (GO:0016328), protein-containing complex (GO:0032991), mitotic spindle pole (GO:0097431), lateral cell cortex (GO:0097575), cell cortex region (GO:0099738), spindle pole (GO:0000922), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein binding	3
mitotic cell cycle	2
cytoplasm	2
cell periphery	2
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
G protein-coupled receptor activity	1
signal transduction	1
response to light stimulus	1
cellular process	1
centrosome localization	1
maintenance of organelle location	1
mitotic spindle organization	1
regulation of spindle organization	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
protein localization to cell cortex	1
positive regulation of protein localization to cell periphery	1
regulation of protein localization to cell cortex	1
spindle assembly	1
positive regulation of cytoskeleton organization	1
positive regulation of cell cycle process	1
regulation of spindle assembly	1
positive regulation of organelle assembly	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
GDP binding	1
GTPase regulator activity	1
protein-containing complex binding	1
binding	1
GTPase activity	1
nucleoside-triphosphatase regulator activity	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1

Protein interactions and networks

STRING

1512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPSM2	NUMA1	Q14980	949
GPSM2	PARD3B	Q8TEW8	903
GPSM2	INSC	Q1MX18	853
GPSM2	PARD3	Q8TEW0	798
GPSM2	SLC25A24	Q6NUK1	765
GPSM2	EPS8	Q12929	759
GPSM2	WHRN	Q9P202	733
GPSM2	MYO15A	Q9UKN7	728
GPSM2	VAV3	Q9UKW4	685
GPSM2	GNAI3	P08754	675
GPSM2	GNAI2	P04899	671
GPSM2	SMPX	Q9UHP9	617
GPSM2	TSPEAR	Q8WU66	608
GPSM2	RIC8A	Q9NPQ8	582
GPSM2	TPRN	Q4KMQ1	580

IntAct

45 interactions, top by confidence:

A	B	Type	Score
GNAI3	GPSM2	psi-mi:“MI:0915”(physical association)	0.670
GPSM2	INSC	psi-mi:“MI:0915”(physical association)	0.670
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
GPSM2	NUMA1	psi-mi:“MI:0915”(physical association)	0.600
NUMA1	GNAI1	psi-mi:“MI:0914”(association)	0.600
NUMA1	GPSM2	psi-mi:“MI:0915”(physical association)	0.600
GPSM2	WHRN	psi-mi:“MI:0915”(physical association)	0.560
GPSM2	GAS2L1	psi-mi:“MI:0915”(physical association)	0.560
GPSM2	ARHGEF40	psi-mi:“MI:0915”(physical association)	0.560
GPSM2	LRRC8E	psi-mi:“MI:0915”(physical association)	0.560
GNAI1	GPSM2	psi-mi:“MI:0915”(physical association)	0.560
GNAI1	GPSM2	psi-mi:“MI:0914”(association)	0.560
GPSM2	GPSM2	psi-mi:“MI:0915”(physical association)	0.550
GPSM2	GPSM2	psi-mi:“MI:2364”(proximity)	0.550
TCEAL1	CHEK1	psi-mi:“MI:0914”(association)	0.530
GPSM2	pins	psi-mi:“MI:0915”(physical association)	0.370
GPSM2	DLG4	psi-mi:“MI:0915”(physical association)	0.370
GPSM2	FXR1	psi-mi:“MI:0915”(physical association)	0.370
GPSM2	FXR2	psi-mi:“MI:0915”(physical association)	0.370
GLIS2	GPSM2	psi-mi:“MI:0915”(physical association)	0.370
GPSM2	AASDH	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): CALD1 (Affinity Capture-MS), ECT2 (Affinity Capture-MS), GTF3C2 (Affinity Capture-MS), TTF1 (Affinity Capture-MS), GEMIN6 (Affinity Capture-MS), PABPC4L (Affinity Capture-MS), AASDH (Affinity Capture-MS), LSM11 (Affinity Capture-MS), GPSM2 (Affinity Capture-RNA), GPSM2 (Proximity Label-MS), GNAI3 (Reconstituted Complex), GPSM2 (Two-hybrid), GNAI2 (Affinity Capture-Western), HRAS (Affinity Capture-Western), GPSM2 (Two-hybrid)

ESM2 similar proteins: A2VDP1, A5D7H2, E9PSK7, E9Q5G3, O14795, O18973, O43815, O55106, O60271, O60447, O88447, O88448, P37285, P46822, P46824, P46825, P58405, P70483, P81274, P83094, P97366, Q02241, Q05090, Q07866, Q13033, Q2HJJ0, Q4KUS2, Q4R8N2, Q58A65, Q5DTM8, Q5PQM2, Q5R581, Q5RAC9, Q5TKA1, Q5VTR2, Q5ZLS3, Q62768, Q676U5, Q68FJ8, Q8BR07

Diamond homologs: P81274, Q6IR34, Q80XJ3, Q86YR5, Q8VDU0, Q96AY4, Q9R080, D3ZSP7, F8RP11, O13797, O16259, O35814, O54981, O88196, P0CT30, P15705, P25407, P31948, P33313, P50503, P53041, P53042, P53804, Q12118, Q2U919, Q32PZ3, Q3ZBZ8, Q43468, Q496Y0, Q49AM3, Q4R8N7, Q4WTC0, Q54DA8, Q5RAP0, Q5XEP2, Q5ZLF0, Q60676, Q60864, Q7ZWU1, Q80ZK9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PBK	up-regulates	GPSM2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	17
Uncertain significance	134
Likely benign	68
Benign	25

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1299315	NM_013296.5(GPSM2):c.832C>T (p.Arg278Ter)	Pathogenic
1823	NM_013296.5(GPSM2):c.379C>T (p.Arg127Ter)	Pathogenic
2778256	NM_013296.5(GPSM2):c.998dup (p.Ala334fs)	Pathogenic
291707	NM_013296.5(GPSM2):c.1473del (p.Phe492fs)	Pathogenic
30781	NM_013296.5(GPSM2):c.1684C>T (p.Gln562Ter)	Pathogenic
3376994	NM_013296.5(GPSM2):c.1002del (p.Ala334_Leu335insTer)	Pathogenic
402258	NM_013296.5(GPSM2):c.977G>A (p.Trp326Ter)	Pathogenic
419261	NM_013296.5(GPSM2):c.1093C>T (p.Arg365Ter)	Pathogenic
419262	NM_013296.5(GPSM2):c.1600+3_1600+6del	Pathogenic
4737904	NM_013296.5(GPSM2):c.666_670dup (p.Ala224delinsValTer)	Pathogenic
500059	NM_013296.5(GPSM2):c.485del (p.Pro162fs)	Pathogenic
523009	NM_013296.5(GPSM2):c.1546_1553del (p.Cys516fs)	Pathogenic
1064650	NM_013296.5(GPSM2):c.858_859delinsGT (p.Tyr286_Ser287delinsTer)	Likely pathogenic
1068248	NM_013296.5(GPSM2):c.557+2T>C	Likely pathogenic
1324510	NM_013296.5(GPSM2):c.1601-2A>G	Likely pathogenic
1324511	NM_013296.5(GPSM2):c.1473_1474delinsAACC (p.Phe492fs)	Likely pathogenic
1333261	NM_013296.5(GPSM2):c.1264-1G>T	Likely pathogenic
1706692	NM_013296.5(GPSM2):c.952A>T (p.Arg318Ter)	Likely pathogenic
180034	NM_013296.5(GPSM2):c.459_460del (p.Ala154fs)	Likely pathogenic
2674617	NM_013296.5(GPSM2):c.681+1G>A	Likely pathogenic
2690987	NM_013296.5(GPSM2):c.1600+3A>C	Likely pathogenic
2758643	NM_013296.5(GPSM2):c.681+2del	Likely pathogenic
3032032	NM_013296.5(GPSM2):c.414+2T>C	Likely pathogenic
3363164	NM_013296.5(GPSM2):c.1337_1338del (p.Phe446fs)	Likely pathogenic
3377596	NM_013296.5(GPSM2):c.1578del (p.Pro528fs)	Likely pathogenic
3773859	NM_013296.5(GPSM2):c.1055C>A (p.Ser352Ter)	Likely pathogenic
445712	NM_013296.5(GPSM2):c.1393C>T (p.Gln465Ter)	Likely pathogenic
4732947	NM_013296.5(GPSM2):c.1263+1G>T	Likely pathogenic
806180	NM_013296.5(GPSM2):c.1194_1198dup (p.Arg400fs)	Likely pathogenic

SpliceAI

3220 predictions. Top by Δscore:

Variant	Effect	Δscore
1:108896862:A:AG	acceptor_gain	1.0000
1:108896863:G:GG	acceptor_gain	1.0000
1:108896863:GA:G	acceptor_gain	1.0000
1:108897480:T:A	acceptor_gain	1.0000
1:108897629:T:G	donor_loss	1.0000
1:108897954:TTTA:T	acceptor_loss	1.0000
1:108897955:TTAGG:T	acceptor_loss	1.0000
1:108897956:TAGG:T	acceptor_loss	1.0000
1:108897957:A:AT	acceptor_loss	1.0000
1:108898099:TGA:T	donor_gain	1.0000
1:108898099:TGAG:T	donor_loss	1.0000
1:108898100:GA:G	donor_gain	1.0000
1:108898100:GAG:G	donor_gain	1.0000
1:108898101:AG:A	donor_loss	1.0000
1:108898102:G:GG	donor_gain	1.0000
1:108898103:TGA:T	donor_loss	1.0000
1:108898104:GAGTA:G	donor_loss	1.0000
1:108898105:AGT:A	donor_loss	1.0000
1:108898878:GC:G	acceptor_gain	1.0000
1:108898993:AAGT:A	donor_loss	1.0000
1:108898995:G:T	donor_loss	1.0000
1:108898996:T:A	donor_loss	1.0000
1:108901785:T:TA	acceptor_gain	1.0000
1:108901786:GTA:G	acceptor_loss	1.0000
1:108901788:A:AG	acceptor_gain	1.0000
1:108901788:AG:A	acceptor_gain	1.0000
1:108901789:G:GG	acceptor_gain	1.0000
1:108901789:GG:G	acceptor_gain	1.0000
1:108901789:GGA:G	acceptor_gain	1.0000
1:108901789:GGAA:G	acceptor_gain	1.0000

AlphaMissense

4529 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:108896887:T:C	L27P	1.000
1:108896890:C:A	A28D	1.000
1:108896898:G:A	G31R	1.000
1:108896898:G:C	G31R	1.000
1:108896898:G:T	G31W	1.000
1:108896899:G:A	G31E	1.000
1:108896935:G:A	G43D	1.000
1:108896955:G:C	A50P	1.000
1:108896989:T:C	L61P	1.000
1:108897000:T:G	Y65D	1.000
1:108897003:A:C	S66R	1.000
1:108897005:C:A	S66R	1.000
1:108897005:C:G	S66R	1.000
1:108897012:G:C	G69R	1.000
1:108897012:G:T	G69C	1.000
1:108897013:G:A	G69D	1.000
1:108897013:G:T	G69V	1.000
1:108897017:T:A	N70K	1.000
1:108897017:T:G	N70K	1.000
1:108897024:T:C	F73L	1.000
1:108897026:C:A	F73L	1.000
1:108897026:C:G	F73L	1.000
1:108897060:C:G	H85D	1.000
1:108897070:A:C	D88A	1.000
1:108897070:A:T	D88V	1.000
1:108897079:T:C	L91P	1.000
1:108897530:G:A	G106D	1.000
1:108897532:A:G	N107D	1.000
1:108897534:T:A	N107K	1.000
1:108897534:T:G	N107K	1.000

dbSNP variants (sampled 300 via entrez): RS1000026820 (1:108910499 G>C), RS1000120063 (1:108904344 A>G,T), RS1000124345 (1:108875991 T>C), RS1000156812 (1:108876088 A>G), RS1000177309 (1:108876485 C>A,T), RS1000207649 (1:108897583 T>G), RS1000249638 (1:108886189 C>T), RS1000263693 (1:108930073 T>C), RS1000320212 (1:108916671 G>A), RS1000335791 (1:108915108 C>T), RS1000354006 (1:108878906 C>T), RS1000391445 (1:108915216 C>A), RS1000472823 (1:108883815 G>C,T), RS1000532665 (1:108884467 CACA>C), RS1000552113 (1:108902855 G>T)

Disease associations

OMIM: gene MIM:609245 | disease phenotypes: MIM:604213, MIM:612555, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
Chudley-McCullough syndrome	Definitive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Chudley-McCullough syndrome	Definitive	AR

Mondo (3): Chudley-McCullough syndrome (MONDO:0011411), breast-ovarian cancer, familial, susceptibility to, 2 (MONDO:0012933), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (5): Chudley-McCullough syndrome (Orphanet:314597), Rare genetic deafness (Orphanet:96210), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001321	Cerebellar hypoplasia
HP:0001338	Partial agenesis of the corpus callosum
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002282	Gray matter heterotopia
HP:0002700	Large foramen magnum
HP:0006989	Dysplastic corpus callosum
HP:0007033	Cerebellar dysplasia
HP:0008625	Severe sensorineural hearing impairment
HP:0100702	Arachnoid cyst

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001343_2	Fat distribution (HIV)	5.000000e-06
GCST001343_5	Fat distribution (HIV)	1.000000e-06
GCST001343_8	Fat distribution (HIV)	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535459	Chudley-Mccullough syndrome (supp.)
C564609	Deafness, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression, decreases expression	5
trichostatin A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Coumestrol	affects cotreatment, increases expression, affects reaction	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	affects expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
bisphenol A	decreases expression	1
methoxyacetic acid	increases expression, increases reaction	1
arsenite	affects binding, decreases reaction	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric oxide	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
palbociclib	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Cisplatin	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1T7	Abcam HeLa GPSM2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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