GEMIN5

Summary

GEMIN5 (gem nuclear organelle associated protein 5, HGNC:20043) is a protein-coding gene on chromosome 5q33.2, encoding Gem-associated protein 5 (Q8TEQ6). The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. It is a common-essential gene (DepMap: required in 99.5% of cancer cell lines).

This gene encodes a WD repeat protein that is a component of the survival of motor neurons (SMN) complex. The SMN complex plays a critical role in mRNA splicing through the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), and may also mediate the assembly and transport of other classes of ribonucleoproteins. The encoded protein is the snRNA-binding component of the SMN complex. Dysregulation of this gene may play a role in alternative mRNA splicing and tumor cell motility. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 25929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 373 total — 13 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_015465

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20043
Approved symbol	GEMIN5
Name	gem nuclear organelle associated protein 5
Location	5q33.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000082516
Ensembl biotype	protein_coding
OMIM	607005
Entrez	25929

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 retained_intron, 1 protein_coding

ENST00000285873, ENST00000522075, ENST00000523355

RefSeq mRNA: 2 — MANE Select: NM_015465 NM_001252156, NM_015465

CCDS: CCDS4330

Canonical transcript exons

ENST00000285873 — 28 exons

Exon	Start	End
ENSE00000768264	154937025	154937185
ENSE00000768265	154935841	154936022
ENSE00000768266	154932099	154932250
ENSE00000768267	154931458	154931577
ENSE00000768271	154924469	154924554
ENSE00000768273	154919967	154920103
ENSE00000815700	154925862	154926074
ENSE00000815704	154917931	154918004
ENSE00000815707	154916998	154917179
ENSE00000815708	154912899	154913038
ENSE00001021068	154898440	154898650
ENSE00001021069	154901339	154901486
ENSE00001021070	154903080	154903175
ENSE00001021094	154891241	154891742
ENSE00001021101	154896092	154896343
ENSE00001021102	154899191	154899310
ENSE00001021105	154902539	154902676
ENSE00001127477	154907591	154907818
ENSE00001127483	154911727	154911898
ENSE00001204649	154904507	154904629
ENSE00001204653	154905363	154905476
ENSE00001204677	154921343	154921425
ENSE00001204685	154927385	154927550
ENSE00001204711	154937968	154938211
ENSE00001303277	154889321	154889417
ENSE00001313506	154892387	154892549
ENSE00001322331	154887411	154888377
ENSE00003620042	154928527	154928659

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 98.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1781 / max 169.5902, expressed in 1791 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64476	19.6810	1783
64475	2.4971	1062

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.60	gold quality
secondary oocyte	CL:0000655	98.49	gold quality
tibialis anterior	UBERON:0001385	88.22	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.52	gold quality
deltoid	UBERON:0001476	84.80	silver quality
ventricular zone	UBERON:0003053	84.60	gold quality
biceps brachii	UBERON:0001507	84.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.83	gold quality
muscle of leg	UBERON:0001383	83.26	gold quality
muscle organ	UBERON:0001630	83.24	gold quality
skeletal muscle organ	UBERON:0014892	83.24	gold quality
gastrocnemius	UBERON:0001388	83.09	gold quality
skeletal muscle tissue	UBERON:0001134	83.03	gold quality
quadriceps femoris	UBERON:0001377	82.88	gold quality
calcaneal tendon	UBERON:0003701	82.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.50	gold quality
vastus lateralis	UBERON:0001379	82.24	gold quality
islet of Langerhans	UBERON:0000006	81.89	gold quality
embryo	UBERON:0000922	81.84	gold quality
ganglionic eminence	UBERON:0004023	81.84	gold quality
muscle tissue	UBERON:0002385	81.80	gold quality
adrenal tissue	UBERON:0018303	81.68	gold quality
cortical plate	UBERON:0005343	81.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.15	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.82	gold quality
stromal cell of endometrium	CL:0002255	79.05	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.05	gold quality
smooth muscle tissue	UBERON:0001135	78.97	gold quality
ileal mucosa	UBERON:0000331	78.66	gold quality
heart left ventricle	UBERON:0002084	78.29	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.80
E-MTAB-6058	no	175.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting GEMIN5, 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-9-5P	100.00	72.28	2361
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-548AU-3P	99.70	68.22	1373

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 26)

• we report the identification of an additional component of the SMN complex, a novel WD repeat protein termed Gemin5. Gemin5 binds SMN directly and is a component of the SMN complex (PMID:11714716)
• Gemin5 is the snRNA binding protein of the SMN complex, binding directly and specifically to the unique features of snRNAs and is the factor that allows the SMN complex to distinguish snRNAs from other cellular RNAs for snRNP biogenesis (PMID:16857593)
• Gemin5 functions as a scaffold protein for the ASK1-JNK1 signaling module and thereby potentiates ASK1-mediated signaling events. (PMID:17541429)
• Absence of GEMIN5 from SMN complexes in nuclear Cajal bodies is demonstrated. (PMID:17640370)
• Gemin5-containing subunits bind small nuclear RNA independently of the SMN complex and without a requirement for exogenous ATP (PMID:17640873)
• The data provide the first demonstration that alterations in the expression of Gemin5, a spliceosome protein, can effect both specific splicing events and tumor cell motility. (PMID:18245461)
• The entire WD repeat domain, comprising 13 WD motifs, is both necessary and sufficient for sequence-specific, high-affinity binding of Gemin5 to its RNA targets. (PMID:19377484)
• gemin5 has a role as a novel cap-binding protein and WD repeat domains are involved in m(7)G recognition (PMID:19750007)
• The Gemin5’s function in delivering pre-snRNAs as substrates for Sm core assembly and processing. (PMID:20513430)
• The C-terminal region of Gemin5 bears two non-canonical bipartite RNA-binding sites. (PMID:24598255)
• This work both reveals a new autoregulatory pathway governing SMN expression, and identifies a new mechanism through which SMN can modulate specific mRNA expression via Gemin5. (PMID:25911097)
• Gemin5 is dispensable for snRNA identification and snRNP assembly. (PMID:26069323)
• These results reveal the ribosome-binding capacity of the N-ter moiety, enabling Gemin5 to control global protein synthesis. (PMID:27507887)
• the WD40 domain of Gemin5 is both necessary and sufficient for binding the Sm site of pre-snRNAs (PMID:27881600)
• provide mechanistic understandings of Gemin5’s snRNA-binding specificity as well as valuable insights into the molecular mechanism of RNA binding by WD40 repeat proteins in general. (PMID:27881601)
• study provides direct evidence that Gemin5 is involved in unassembled-U1 snRNA disposal under conditions of SMN deficiency. (PMID:29537490)
• The non-canonical RNA-binding domains of gem nuclear organelle associated protein 5 (Gemin5) recognize distinct RNAs. (PMID:29771365)
• The characterization of this unanticipated dimerization domain provides the structural basis for a role of the middle region of Gemin5 as a central hub for protein-protein interactions. (PMID:31799608)
• Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder. (PMID:33963192)
• Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy. (PMID:34569062)
• Functional and structural deficiencies of Gemin5 variants associated with neurological disorders. (PMID:35393353)
• A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy. (PMID:36980979)
• SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration. (PMID:37369805)
• Mutations of GEMIN5 are associated with coenzyme Q10 deficiency: long-term follow-up after treatment. (PMID:38316953)
• Expanding the clinical phenotype and genetic spectrum of GEMIN5 disorders: Early-infantile developmental and epileptic encephalopathies. (PMID:38773790)
• Alternative splicing events driven by altered levels of GEMIN5 undergo translation. (PMID:39194147)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gemin5	ENSDARG00000079257
mus_musculus	Gemin5	ENSMUSG00000037275
rattus_norvegicus	Gemin5	ENSRNOG00000002645

Paralogs (9): ERCC8 (ENSG00000049167), RBBP7 (ENSG00000102054), WDR59 (ENSG00000103091), GRWD1 (ENSG00000105447), PEX7 (ENSG00000112357), WDR77 (ENSG00000116455), WDR24 (ENSG00000127580), RBBP4 (ENSG00000162521), WDR73 (ENSG00000177082)

Protein

Protein identifiers

Gem-associated protein 5 — Q8TEQ6 (reviewed: Q8TEQ6)

All UniProt accessions (1): Q8TEQ6

UniProt curated annotations — full annotation on UniProt →

Function. The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm ultimately triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP. Within the SMN complex, GEMIN5 recognizes and delivers the small nuclear RNAs (snRNAs) to the SMN complex. Binds to the 7-methylguanosine cap of RNA molecules (PubMed:19750007, PubMed:27834343, PubMed:27881600, PubMed:27881601, Ref.27). Binds to the 3’-UTR of SMN1 mRNA and regulates its translation; does not affect mRNA stability. May play a role in the regulation of protein synthesis via its interaction with ribosomes.

Subunit / interactions. Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP. Part of the SMN-Sm complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8, STRAP/UNRIP and the Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG. Interacts with GEMIN2; the interaction is direct. Interacts with SMN1, SNRPB, SNRPD1, SNRPD2, SNRPD3 and SNRPE; the interaction is direct. Interacts with cytosolic DDX20/GEMIN3 and GEMIN4. Interacts with SNRNP70 and HNRNPU. Identified in a complex with 80S ribosomes; binds to the 60S large ribosomal subunit. Interacts with the ribosomal subunits RPL3 and RPL4.

Subcellular location. Nucleus. Nucleoplasm. Gem. Cytoplasm.

Disease relevance. Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) [MIM:619333] An autosomal recessive disorder characterized by global developmental delay with predominantly motor abnormalities, axial hypotonia with decreased or absent reflexes, gait ataxia and appendicular spasticity. Affected individuals have cognitive impairment and speech delay. Brain imaging shows cerebellar atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WD repeat domain mediates binding to U1 snRNA and to U4 snRNA. The WD repeat domain also mediates binding to the 7-methylguanosine cap that is found both on mRNA and snRNA molecules (PubMed:19750007, PubMed:27834343, PubMed:27881600, PubMed:27881601, Ref.27). The regions that bind snRNA molecules and the isolated 7-methylguanosine cap overlap at least partially. Besides, the WD repeat domain mediates interaction with the 60S large ribosomal subunit.

Similarity. Belongs to the WD repeat gemin-5 family.

RefSeq proteins (2): NP_001239085, NP_056280* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR052640	Gemin-5	Family
IPR056420	GEMI5_RBS	Domain
IPR056421	TPR_GEMI5	Domain
IPR056424	Beta-prop_GEMI5_2nd	Domain
IPR056432	Beta-prop_GEMI5_1st	Domain

Pfam: PF00400, PF23770, PF23774, PF23775, PF23777

UniProt features (221 total): strand 72, helix 47, sequence variant 26, mutagenesis site 16, site 14, repeat 13, turn 13, modified residue 8, region of interest 5, compositionally biased region 2, sequence conflict 2, chain 1, coiled-coil region 1, cross-link 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
5TEE	X-RAY DIFFRACTION	1.65
5GXH	X-RAY DIFFRACTION	1.8
5THA	X-RAY DIFFRACTION	1.8
5GXI	X-RAY DIFFRACTION	1.85
5H1K	X-RAY DIFFRACTION	1.9
5TEF	X-RAY DIFFRACTION	1.95
6RNQ	X-RAY DIFFRACTION	1.95
5H1J	X-RAY DIFFRACTION	2
5H1L	X-RAY DIFFRACTION	2.1
5H1M	X-RAY DIFFRACTION	2.49
5H3U	X-RAY DIFFRACTION	2.5
5H3T	X-RAY DIFFRACTION	2.57
7XGR	ELECTRON MICROSCOPY	2.6
6RNS	X-RAY DIFFRACTION	2.69
5H3S	X-RAY DIFFRACTION	3
7XDT	ELECTRON MICROSCOPY	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEQ6-F1	79.17	0.46

Functional residue map

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

Catalytic / active sites (14): 33 (interaction with u4 snrna); 284 (interaction with u4 snrna); 335 (interaction with u4 snrna); 359 (interaction with u4 snrna); 381 (interaction with u4 snrna); 422 (interaction with u4 snrna); 426 (interaction with u4 snrna); 470 (interaction with u4 snrna); 474 (interaction with u4 snrna and with the 7-methylguanosine cap of rna molecules); 556 (interaction with u4 snrna); 579 (interaction with u4 snrna); 641 (interaction with u4 snrna and with the 7-methylguanosine cap of rna molecules) …

Post-translational modifications (9): 48, 51, 624, 751, 757, 770, 778, 847, 754

Mutagenesis-validated functional residues (16):

Position	Phenotype
14	abolishes interaction with u4 snrna. no effect on interaction with the isolated 7-methylguanosine cap that is normally p
15	abolishes interaction with u4 snrna. no effect on interaction with the isolated 7-methylguanosine cap that is normally p
33	abolishes interaction with u4 snrna.
197	abolishes interaction with u4 snrna.
271–273	no effect in interaction with u4 snrna. no effect on interaction with smn complex.
286	abolishes interaction with u4 snrna. abolishes interaction with the 7-methylguanosine cap of rna molecules. no effect on
290	no effect in interaction with u4 snrna. no effect on interaction with smn complex.
335	abolishes interaction with u4 snrna.
359	abolishes interaction with u4 snrna.
381	strongly decreases interaction with u4 snrna. no effect on interaction with the isolated 7-methylguanosine cap that is n
381	abolishes interaction with u4 snrna.
422	abolishes interaction with u4 snrna.
474	abolishes interaction with the isolated 7-methylguanosine cap that is normally part of rna molecules.
641	abolishes interaction with the isolated 7-methylguanosine cap that is normally part of rna molecules.
660	abolishes interaction with the isolated 7-methylguanosine cap that is normally part of rna molecules.
684	abolishes interaction with the isolated 7-methylguanosine cap that is normally part of rna molecules.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-191859	snRNP Assembly
R-HSA-9754678	SARS-CoV-2 modulates host translation machinery

MSigDB gene sets: 177 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_CIS, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GOBP_SPLICEOSOMAL_SNRNP_ASSEMBLY, REACTOME_METABOLISM_OF_RNA, GOCC_RNA_POLYMERASE_II_TRANSCRIPTION_REGULATOR_COMPLEX, GOCC_SMN_COMPLEX, GOCC_GEMINI_OF_CAJAL_BODIES

GO Biological Process (7): spliceosomal snRNP assembly (GO:0000387), mRNA splicing, via spliceosome (GO:0000398), translation (GO:0006412), regulation of translation (GO:0006417), protein-containing complex assembly (GO:0065003), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (9): RNA 7-methylguanosine cap binding (GO:0000340), RNA binding (GO:0003723), mRNA 3’-UTR binding (GO:0003730), snRNA binding (GO:0017069), U1 snRNA binding (GO:0030619), U4 snRNA binding (GO:0030621), U4atac snRNA binding (GO:0030622), ribosome binding (GO:0043022), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604), SMN complex (GO:0032797), SMN-Gemin2 complex (GO:0034718), SMN-Sm protein complex (GO:0034719), Gemini of Cajal bodies (GO:0097504)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of non-coding RNA	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
snRNA binding	3
Sm-like protein family complex	3
RNA processing	2
cytoplasm	2
mRNA splicing, via spliceosome	1
protein-RNA complex assembly	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cellular component assembly	1
protein-containing complex organization	1
mRNA metabolic process	1
RNA cap binding	1
nucleic acid binding	1
mRNA binding	1
RNA binding	1
ribonucleoprotein complex binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
SMN-Sm protein complex	1
RNA polymerase II transcription regulator complex	1
SMN complex	1
nuclear body	1

Protein interactions and networks

STRING

2228 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GEMIN5	GEMIN2	O14893	998
GEMIN5	DDX20	Q9UHI6	998
GEMIN5	GEMIN4	P57678	993
GEMIN5	GEMIN6	Q8WXD5	988
GEMIN5	GEMIN7	Q9H840	937
GEMIN5	EIF4E	P06730	934
GEMIN5	GEMIN8	Q9NWZ8	894
GEMIN5	STRAP	Q9Y3F4	881
GEMIN5	PHAX	Q9H814	689
GEMIN5	SYNCRIP	O60506	687
GEMIN5	COIL	P38432	652
GEMIN5	LSM10	Q969L4	608
GEMIN5	KHSRP	Q92945	604
GEMIN5	SNRPB	P14678	589
GEMIN5	XRN1	Q8IZH2	582

IntAct

197 interactions, top by confidence:

A	B	Type	Score
SMN1	GEMIN2	psi-mi:“MI:0914”(association)	0.960
PDCD6IP	CEP55	psi-mi:“MI:0914”(association)	0.960
SNRPF	GEMIN2	psi-mi:“MI:0914”(association)	0.910
GEMIN5	SNRPE	psi-mi:“MI:0915”(physical association)	0.770
SNRPE	GEMIN2	psi-mi:“MI:0914”(association)	0.770
GEMIN5	SMN1	psi-mi:“MI:0915”(physical association)	0.730
SMN1	GEMIN5	psi-mi:“MI:0403”(colocalization)	0.730
GEMIN5	SNRPB	psi-mi:“MI:0914”(association)	0.730
SMN1	GEMIN5	psi-mi:“MI:0915”(physical association)	0.730
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
SNRPG	GEMIN2	psi-mi:“MI:0914”(association)	0.710
MAD2L1	INSR	psi-mi:“MI:0914”(association)	0.700
SNRPB	PRMT5	psi-mi:“MI:0914”(association)	0.670
SNRPA1	HTATSF1	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCKIPSD	GEMIN2	psi-mi:“MI:0914”(association)	0.640
SNRNP70	GEMIN2	psi-mi:“MI:0914”(association)	0.640
SNRPA1	U2SURP	psi-mi:“MI:0914”(association)	0.640
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
SMN1	PRMT5	psi-mi:“MI:0914”(association)	0.600

BioGRID (380): GEMIN5 (Affinity Capture-RNA), GEMIN5 (Affinity Capture-RNA), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-Western), DDX20 (Affinity Capture-Western), WHSC1 (Affinity Capture-Western), GEMIN5 (Affinity Capture-Western), GEMIN5 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), GEMIN5 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2KIZ8, A0A1L8GXY4, A0A571BF63, A0A8M9QN10, A2CEI4, A2RRP1, A4D1P6, A6H8T2, A9X1C6, B0FXQ5, B1WC10, B2KIQ4, B2RY71, B2RYI0, B7FF09, B7FF12, E9PYY5, F1QHZ6, Q1LXZ7, Q2HJE1, Q3UMY5, Q402B2, Q4V8G4, Q5R6T6, Q5RE88, Q5U1Z0, Q5VTH9, Q5XIZ9, Q5ZLL7, Q6DFC6, Q6DTM3, Q6GPB9, Q6P2C0, Q6TEN6, Q7TMQ7, Q7ZVR1, Q8BMG7, Q8BX17, Q8C147, Q8IWG1

Diamond homologs: A0A223GEB2, A0CH87, A0DB19, A1D3F5, A5D7H2, A5DWF4, A6H603, A6NE52, A6QX61, A6RRD4, A6ZZZ8, A8XYW9, B0XAF3, B0XQ42, B8M0Q1, B8N9H4, C0S902, C4R6H3, G0SCK6, G1SJB4, G4MQX3, O18640, O24076, O24456, O42248, O42249, O54927, O54929, O60508, O94527, P07834, P0CS44, P0CS45, P25387, P36130, P38011, P46800, P49026, P49027, P58405

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GEMIN5	“form complex”	“SMN complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 196 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
Metabolism of non-coding RNA	9	41.1×	2e-11
SARS-CoV-2 modulates host translation machinery	15	24.2×	3e-15
snRNP Assembly	15	22.8×	5e-15
mRNA Splicing	19	15.0×	3e-15
RNA Polymerase II Transcription Termination	9	14.2×	5e-07
mRNA Polyadenylation	21	13.3×	1e-15
Processing of Capped Intron-Containing Pre-mRNA	21	12.4×	3e-15
mRNA Splicing - Minor Pathway	7	11.3×	9e-05

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal snRNP assembly	17	56.8×	4e-24
U2-type prespliceosome assembly	10	35.9×	3e-11
spliceosomal complex assembly	6	20.8×	7e-05
translational initiation	7	14.4×	8e-05
mRNA splicing, via spliceosome	24	12.6×	5e-17
RNA splicing	16	8.1×	3e-08
negative regulation of translation	7	7.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	21
Uncertain significance	263
Likely benign	27
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1120192	NM_015465.5(GEMIN5):c.2738A>G (p.His913Arg)	Pathogenic
1120193	NM_015465.5(GEMIN5):c.3356T>C (p.Leu1119Ser)	Pathogenic
1120194	NM_015465.5(GEMIN5):c.1602C>A (p.Tyr534Ter)	Pathogenic
1120195	NM_015465.5(GEMIN5):c.282G>A (p.Trp94Ter)	Pathogenic
1120196	NM_015465.5(GEMIN5):c.3856T>A (p.Tyr1286Asn)	Pathogenic
1120197	NM_015465.5(GEMIN5):c.2998T>C (p.Ser1000Pro)	Pathogenic
1120198	NM_015465.5(GEMIN5):c.3203T>C (p.Leu1068Pro)	Pathogenic
2290228	NM_015465.5(GEMIN5):c.119del (p.Arg40fs)	Pathogenic
2300728	NM_015465.5(GEMIN5):c.3429del (p.Ser1144fs)	Pathogenic
2468837	NM_015465.5(GEMIN5):c.3931dup (p.Ser1311fs)	Pathogenic
2655980	NM_015465.5(GEMIN5):c.1045A>T (p.Lys349Ter)	Pathogenic
4535197	NM_015465.5(GEMIN5):c.1200_1201del (p.Asp401fs)	Pathogenic
4536295	NM_015465.5(GEMIN5):c.2224A>T (p.Lys742Ter)	Pathogenic
1192206	NM_015465.5(GEMIN5):c.2768A>C (p.His923Pro)	Likely pathogenic
1317180	NM_015465.5(GEMIN5):c.819AGG[1] (p.Gly276del)	Likely pathogenic
1328172	NM_015465.5(GEMIN5):c.2962A>T (p.Ile988Phe)	Likely pathogenic
1703188	NM_015465.5(GEMIN5):c.1267C>T (p.Gln423Ter)	Likely pathogenic
1709185	NM_015465.5(GEMIN5):c.3973_3974insC (p.Glu1325fs)	Likely pathogenic
2584965	NM_015465.5(GEMIN5):c.2883G>A (p.Trp961Ter)	Likely pathogenic
2630379	NM_015465.5(GEMIN5):c.3153_3160dup (p.Asp1054fs)	Likely pathogenic
2631551	NM_015465.5(GEMIN5):c.4100T>C (p.Leu1367Pro)	Likely pathogenic
3340264	NM_015465.5(GEMIN5):c.1856del (p.Glu619fs)	Likely pathogenic
3375749	NM_015465.5(GEMIN5):c.778C>T (p.Arg260Ter)	Likely pathogenic
3383323	NM_015465.5(GEMIN5):c.1081-2A>G	Likely pathogenic
3383358	NM_015465.5(GEMIN5):c.4263-1G>C	Likely pathogenic
3383566	NM_015465.5(GEMIN5):c.1995+1G>A	Likely pathogenic
3776223	NM_015465.5(GEMIN5):c.167-3_167-2del	Likely pathogenic
3778292	NM_015465.5(GEMIN5):c.730A>G (p.Thr244Ala)	Likely pathogenic
3900667	NM_015465.5(GEMIN5):c.754C>T (p.Arg252Ter)	Likely pathogenic
4527635	NM_015465.5(GEMIN5):c.414G>A (p.Trp138Ter)	Likely pathogenic

SpliceAI

3796 predictions. Top by Δscore:

Variant	Effect	Δscore
5:154888373:CAGGC:C	acceptor_gain	1.0000
5:154889316:CTTA:C	donor_loss	1.0000
5:154889317:TTAC:T	donor_loss	1.0000
5:154889318:TA:T	donor_loss	1.0000
5:154889319:ACCTT:A	donor_loss	1.0000
5:154889320:C:CA	donor_loss	1.0000
5:154889413:CTTTA:C	acceptor_gain	1.0000
5:154889414:TTTA:T	acceptor_gain	1.0000
5:154889415:TTA:T	acceptor_gain	1.0000
5:154889416:TA:T	acceptor_gain	1.0000
5:154889416:TACT:T	acceptor_loss	1.0000
5:154889417:ACTAG:A	acceptor_loss	1.0000
5:154889418:C:CA	acceptor_loss	1.0000
5:154889418:C:CC	acceptor_gain	1.0000
5:154889421:G:C	acceptor_gain	1.0000
5:154889421:G:GC	acceptor_gain	1.0000
5:154891739:CAGC:C	acceptor_gain	1.0000
5:154892383:TTACC:T	donor_loss	1.0000
5:154892385:A:AC	donor_gain	1.0000
5:154892385:AC:A	donor_gain	1.0000
5:154892385:ACCGT:A	donor_gain	1.0000
5:154892386:C:CG	donor_gain	1.0000
5:154892386:CC:C	donor_gain	1.0000
5:154892386:CCG:C	donor_gain	1.0000
5:154892386:CCGT:C	donor_gain	1.0000
5:154892386:CCGTC:C	donor_gain	1.0000
5:154892413:T:TA	donor_gain	1.0000
5:154892545:AGGAG:A	acceptor_gain	1.0000
5:154892546:GGAG:G	acceptor_gain	1.0000
5:154892547:GAG:G	acceptor_gain	1.0000

AlphaMissense

9873 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:154927534:A:G	W311R	1.000
5:154927534:A:T	W311R	1.000
5:154899197:G:T	A1043D	0.999
5:154901399:A:G	L985P	0.999
5:154911766:A:G	W710R	0.999
5:154911766:A:T	W710R	0.999
5:154911826:A:G	W690R	0.999
5:154911826:A:T	W690R	0.999
5:154911895:A:G	W667R	0.999
5:154911895:A:T	W667R	0.999
5:154912903:G:T	A664D	0.999
5:154912955:A:G	W647R	0.999
5:154912955:A:T	W647R	0.999
5:154917097:A:G	W586R	0.999
5:154917097:A:T	W586R	0.999
5:154920066:G:C	S500R	0.999
5:154920066:G:T	S500R	0.999
5:154920068:T:G	S500R	0.999
5:154921373:A:G	W478R	0.999
5:154921373:A:T	W478R	0.999
5:154924502:C:A	G449V	0.999
5:154924502:C:T	G449E	0.999
5:154924514:C:T	G445E	0.999
5:154925869:A:T	V429D	0.999
5:154925941:C:G	R405P	0.999
5:154926065:A:G	W364R	0.999
5:154926065:A:T	W364R	0.999
5:154927388:T:A	R359S	0.999
5:154927388:T:G	R359S	0.999
5:154927389:C:A	R359I	0.999

dbSNP variants (sampled 300 via entrez): RS1000166885 (5:154917713 G>A,T), RS1000282536 (5:154887542 A>G), RS1000318567 (5:154899804 T>C), RS1000364936 (5:154918074 A>T), RS1000368141 (5:154893754 GTTTTT>G,GTTTT,GTTTTTT), RS1000475332 (5:154935243 T>C), RS1000517238 (5:154924661 G>C), RS1000537817 (5:154900027 T>G), RS1000576230 (5:154930599 A>C,G), RS1000585817 (5:154922701 T>C,G), RS1000688697 (5:154914561 T>G), RS1000722574 (5:154923947 C>T), RS1000850399 (5:154934374 C>A,G,T), RS1000902298 (5:154893925 G>A), RS1000933207 (5:154894152 C>T)

Disease associations

OMIM: gene MIM:607005 | disease phenotypes: MIM:619333, MIM:190300

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with cerebellar atrophy and motor dysfunction	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with cerebellar atrophy and motor dysfunction	Definitive	AR

Mondo (2): neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (MONDO:0859152), essential tremor (MONDO:0003233)

Orphanet (1): NON RARE IN EUROPE: Hereditary essential tremor (Orphanet:862)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001348	Brisk reflexes
HP:0002540	Inability to walk
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0011463	Childhood onset
HP:0012389	Appendicular hypotonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009936_9	Venous thromboembolism	9.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020329	Essential Tremor	C10.228.662.350

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724688 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.63	Kd	232.4	nM	CHEMBL5653589
6.63	ED50	232.4	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148426: Binding affinity to human GEMIN5 incubated for 45 mins by Kinobead based pull down assay	kd	0.2324	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases activity, affects cotreatment, increases abundance, increases expression	4
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cadmium Chloride	decreases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	increases expression	1
coumarin	decreases phosphorylation	1
cupric oxide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
picoxystrobin	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Antimycin A	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Copper	affects binding, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651468	Binding	Binding affinity to human GEMIN5 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00439699	PHASE4	COMPLETED	A Pilot Clinical Trial Of Memantine for Essential Tremor
NCT00584376	PHASE4	COMPLETED	Pregabalin (Lyrica) for the Treatment of Essential Tremor
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02111369	PHASE4	COMPLETED	Propranolol and Botulinum Toxin for Essential Vocal Tremor
NCT02495883	PHASE4	COMPLETED	Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
NCT00018564	PHASE3	COMPLETED	Novel Therapies for Essential Tremor
NCT00236496	PHASE3	COMPLETED	A Comparison of the Efficacy and Safety of Topiramate Versus Placebo in Treating Tremor of Unknown Cause.
NCT01441284	PHASE3	WITHDRAWN	Efficacy of Pramipexole Extended Release in the Treatment of Essential Tremor
NCT04193527	PHASE3	COMPLETED	A Study to Evaluate the Diagnostic Efficacy of DaTSCAN™ Ioflupane (123I) Injection in Single Photon Emission Computed Tomography (SPECT) for the Diagnosis of Parkinsonian Syndrome (PS) in Chinese Patients
NCT04265209	PHASE3	COMPLETED	[18F] LBT-999 PET Compared to [123I]-FP/CIT SPECT to Distinguish Between Parkinson’s Diseases and Essential Tremor
NCT06087276	PHASE3	ENROLLING_BY_INVITATION	Essential 3 - Decentralized, Phase 3 Study Evaluating the Safety and Efficacy of Ulixacaltamide in Essential Tremor (ET)
NCT00080366	PHASE2	COMPLETED	Octanol to Treat Essential Tremor
NCT00102596	PHASE2	COMPLETED	Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
NCT00223743	PHASE2	COMPLETED	A Safety/Efficacy Trial of Zonisamide for Essential Tremor
NCT00321087	PHASE2	TERMINATED	A Study of T2000 in Essential Tremor
NCT00598078	PHASE2	COMPLETED	Multiple-dose,Double-blind,Placebo-controlled Study of Sodium Oxybate in Patients With Essential Tremor
NCT00655278	PHASE2	TERMINATED	T2000 in Essential Tremor - Open Label Continuation
NCT01332695	PHASE2	COMPLETED	A Pilot Efficacy and Safety Study of ST101 in Essential Tremor
NCT02277106	PHASE2	COMPLETED	Evaluate SAGE-547 in Participants With Essential Tremor
NCT02551848	PHASE2	UNKNOWN	Kinematic-based BoNT-A Injections for Bilateral ET
NCT02668146	PHASE2	UNKNOWN	An Efficacy/Safety Study of Perampanel for Reducing Essential Tremor
NCT02978781	PHASE2	COMPLETED	A Study to Evaluate SAGE-217 in Participants With Essential Tremor
NCT03101241	PHASE2	COMPLETED	A Phase 2 RCT Study of CX-8998 for Essential Tremor
NCT03688685	PHASE2	COMPLETED	A Clinical Study to Evaluate CAD-1883 in Essential Tremor
NCT03780426	PHASE2	COMPLETED	tSMS in Essential Tremor
NCT04305275	PHASE2	COMPLETED	A Study to Evaluate the Efficacy, Safety, and Tolerability of SAGE-324 in Participants With Essential Tremor
NCT04727658	PHASE2	TERMINATED	Linac FRACtionated Radiosurgical THALamotomie in Tremors (FRACTHAL)
NCT04880616	PHASE2	COMPLETED	Safety, Efficacy, and Tolerability of NBI-827104 for the Treatment of Essential Tremor
NCT05021978	PHASE2	COMPLETED	A Clinical Trial of PRAX-944 in Participants With Essential Tremor
NCT05021991	PHASE2	COMPLETED	A Clinical Trial of 2 Doses of PRAX-944 in Participants With Essential Tremor
NCT05122650	PHASE2	COMPLETED	A Study To Assess the Safety and Efficacy of JZP385 in the Treatment of Adults With Moderate to Severe Essential Tremor (ET)
NCT05173012	PHASE2	COMPLETED	Study to Evaluate SAGE-324 in Participants With Essential Tremor
NCT05387642	PHASE2	WITHDRAWN	A Clinical Trial of PRAX-114 in Participants With Essential Tremor
NCT06312800	PHASE2	WITHDRAWN	Acamprosate and Methazolamide for Essential Tremor
NCT06821906	PHASE2	RECRUITING	Stereotactic Radiosurgery in the Treatment of Essential Tremor
NCT07074002	PHASE2	RECRUITING	Proof of Concept Study on BP1.4979 Effect on Essential Tremor
NCT07103265	PHASE2	NOT_YET_RECRUITING	Developing a New LIFU Neuromodulation Method to Suppress Tremor
NCT00001986	PHASE1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT00016679	PHASE1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT01304758	PHASE1	COMPLETED	ExAblate Transcranial MR Guided Focused Ultrasound in the Treatment of Essential Tremor