GEMIN4

Summary

GEMIN4 (gem nuclear organelle associated protein 4, HGNC:15717) is a protein-coding gene on chromosome 17p13.3, encoding Gem-associated protein 4 (P57678). 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 selective cancer dependency (DepMap: 78.0% of cell lines).

The product of this gene is part of a large complex localized to the cytoplasm, nucleoli, and to discrete nuclear bodies called Gemini bodies (gems). The complex functions in spliceosomal snRNP assembly in the cytoplasm, and regenerates spliceosomes required for pre-mRNA splicing in the nucleus. The encoded protein directly interacts with a DEAD box protein and several spliceosome core proteins. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

Source: NCBI Gene 50628 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 338 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 78.0% of screened cell lines
• MANE Select transcript: NM_015721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15717
Approved symbol	GEMIN4
Name	gem nuclear organelle associated protein 4
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	HHRF-1, DKFZP434B131, p97, DKFZP434D174, HC56, HCAP1
Ensembl gene	ENSG00000179409
Ensembl biotype	protein_coding
OMIM	606969
Entrez	50628

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000319004, ENST00000437269, ENST00000570364, ENST00000573482, ENST00000574958, ENST00000576383, ENST00000576778

RefSeq mRNA: 1 — MANE Select: NM_015721 NM_015721

CCDS: CCDS45559

Canonical transcript exons

ENST00000319004 — 2 exons

Exon	Start	End
ENSE00001278885	744421	748032
ENSE00001540566	752133	752264

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 92.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.9310 / max 110.6847, expressed in 1794 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163640	8.2172	1762
163639	4.3634	1506
163637	3.1253	1195
163638	0.7229	477
163642	0.3978	199
163641	0.1044	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	92.98	gold quality
left testis	UBERON:0004533	92.21	gold quality
right testis	UBERON:0004534	92.05	gold quality
male germ cell	CL:0000015	91.78	gold quality
testis	UBERON:0000473	90.88	gold quality
skin of abdomen	UBERON:0001416	88.82	gold quality
skin of leg	UBERON:0001511	88.52	gold quality
cervix squamous epithelium	UBERON:0006922	88.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.83	gold quality
zone of skin	UBERON:0000014	87.29	gold quality
gingival epithelium	UBERON:0001949	85.23	gold quality
left ovary	UBERON:0002119	84.50	gold quality
body of stomach	UBERON:0001161	84.35	gold quality
right ovary	UBERON:0002118	84.25	gold quality
squamous epithelium	UBERON:0006914	84.08	gold quality
right lobe of thyroid gland	UBERON:0001119	83.93	gold quality
right coronary artery	UBERON:0001625	83.90	gold quality
adult organism	UBERON:0007023	83.70	gold quality
gingiva	UBERON:0001828	83.60	gold quality
gastrocnemius	UBERON:0001388	83.48	gold quality
gall bladder	UBERON:0002110	83.43	gold quality
esophagus mucosa	UBERON:0002469	83.36	gold quality
ovary	UBERON:0000992	83.35	gold quality
left lobe of thyroid gland	UBERON:0001120	83.32	gold quality
thyroid gland	UBERON:0002046	83.16	gold quality
stomach	UBERON:0000945	82.97	gold quality
muscle of leg	UBERON:0001383	82.85	gold quality
body of uterus	UBERON:0009853	82.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.64	gold quality
apex of heart	UBERON:0002098	82.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting GEMIN4, 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-4776-3P	100.00	68.73	1340
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-27A-5P	97.01	65.63	528
HSA-MIR-6846-3P	94.80	65.19	389
HSA-MIR-6089	89.72	61.35	324

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 78.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• zinc-finger proteins were identified as HCAP1-interacting proteins (PMID:12869526)
• A haplotype of HCAP1 with minor alleles at 5 single nucleotide polymorphisms may be related to cancer susceptibility: its expression causes up-regulation of genes involved in cell growth and down-regulation of genes involved in apoptosis and DNA repair. (PMID:14603441)
• Gemin3 and Gemin4 function in Sm core assembly and correlate the activity of this pathway with Spinal Muscular Atrophy. (PMID:16301532)
• A canonical nuclear import sequence in the N-terminus of Gemin4 was identified. (PMID:18675250)
• the association between the GEMIN4 gene and the risk of prostate cancer (PMID:22506892)
• These findings indicate that GEMIN4 functions as a novel coregulator of the MR. (PMID:25555524)
• We selected five single nucleotide polymorphisms (SNPs) (rs7813, rs2740349, rs2291778, rs910924, rs595961) in two key microRNA biosynthesis genes (GEMIN4 and AGO1) and systematically evaluated the association between these SNPs, the gene-environment interaction and lung cancer risk. This is the first study showing that rs7813 and rs595961 could be meaningful as genetic markers for lung cancer risk. (PMID:27669275)
• A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts. (PMID:35052432)
• Association of GEMIN4 gene polymorphisms with the risk of colorectal cancer in the Polish population. (PMID:35384865)
• Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome. (PMID:35861185)
• GEMIN4 Variants: Risk Profiling, Bioinformatics, and Dynamic Simulations Uncover Susceptibility to Bladder Carcinoma. (PMID:38401326)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gemin4	ENSDARG00000041252
mus_musculus	Gemin4	ENSMUSG00000049396
rattus_norvegicus	Gemin4	ENSRNOG00000055236

Protein

Protein identifiers

Gem-associated protein 4 — P57678 (reviewed: P57678)

Alternative names: Component of gems 4, p97

All UniProt accessions (7): P57678, E7EN12, I3L1J7, I3L2C7, I3L399, I3L4A4, I3L4M4

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 triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP.

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 GEMIN3; the interaction is direct. Interacts with GEMIN5. Interacts with GEMIN8; the interaction is direct. Interacts with several snRNP SM core proteins, including SNRPB, SNRPD1, SNRPD2, SNRPD3 and SNRPE. Interacts with PPP4R2.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Gem.

Disease relevance. Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (NEDMCR) [MIM:617913] An autosomal recessive, severe neurodevelopmental disorder characterized by global developmental delay since infancy, microcephaly, poor or absent speech, and inability to walk or spasticity. Additional features include renal abnormalities, congenital cataracts, gastroesophageal reflux disease, seizures with onset in infancy or childhood, hyporeflexia, and non-specific white matter abnormalities on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_056536* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033265	GEMIN4	Family

UniProt features (23 total): sequence variant 12, sequence conflict 5, modified residue 4, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57678-F1	84.54	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.

Post-translational modifications (4): 1, 84, 86, 205

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: 260 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_YELLOW_DN, GOBP_RIBOSOME_BIOGENESIS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GGCNKCCATNK_UNKNOWN, KMCATNNWGGA_UNKNOWN, ZIC1_01, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, GARY_CD5_TARGETS_DN, SCHLOSSER_MYC_TARGETS_AND_SERUM_RESPONSE_UP, TIEN_INTESTINE_PROBIOTICS_24HR_UP, HAN_SATB1_TARGETS_DN, CHEN_HOXA5_TARGETS_9HR_DN, GGCNNMSMYNTTG_UNKNOWN

GO Biological Process (4): spliceosomal snRNP assembly (GO:0000387), rRNA processing (GO:0006364), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (2): ribonucleoprotein complex binding (GO:0043021), protein binding (GO:0005515)

GO Cellular Component (13): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), Cajal body (GO:0015030), membrane (GO:0016020), nuclear body (GO:0016604), small nuclear ribonucleoprotein complex (GO:0030532), SMN complex (GO:0032797), SMN-Sm protein complex (GO:0034719), extracellular exosome (GO:0070062), Gemini of Cajal bodies (GO:0097504), nucleus (GO:0005634)

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
RNA processing	3
Sm-like protein family complex	3
nuclear lumen	2
intracellular membraneless organelle	2
cytoplasm	2
mRNA splicing, via spliceosome	1
protein-RNA complex assembly	1
rRNA metabolic process	1
ribosome biogenesis	1
mRNA metabolic process	1
protein-containing complex binding	1
binding	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1
nucleoplasm	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
SMN-Sm protein complex	1
SMN complex	1
extracellular vesicle	1
nuclear body	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GEMIN4	DDX20	Q9UHI6	999
GEMIN4	GEMIN2	O14893	998
GEMIN4	AGO2	Q9UKV8	997
GEMIN4	GEMIN5	Q8TEQ6	993
GEMIN4	GEMIN6	Q8WXD5	941
GEMIN4	LGALS3	P17931	926
GEMIN4	GEMIN7	Q9H840	881
GEMIN4	TARBP2	Q15633	805
GEMIN4	GEMIN8	Q9NWZ8	773
GEMIN4	PPP4R2	Q9NY27	725
GEMIN4	AGO1	Q9UL18	702
GEMIN4	DICER1	Q9UPY3	696
GEMIN4	SMN1	Q16637	664
GEMIN4	TNRC6B	Q9UPQ9	641
GEMIN4	VPS53	Q5VIR6	624

IntAct

326 interactions, top by confidence:

A	B	Type	Score
SMN1	GEMIN2	psi-mi:“MI:0914”(association)	0.960
GEMIN4	DDX20	psi-mi:“MI:0915”(physical association)	0.910
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
SPRY1	GEMIN4	psi-mi:“MI:0915”(physical association)	0.670
GEMIN4	SPRY1	psi-mi:“MI:0915”(physical association)	0.670
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCKIPSD	GEMIN2	psi-mi:“MI:0914”(association)	0.640
SMN1	PRMT5	psi-mi:“MI:0914”(association)	0.600
PSMB1	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
PTCD1	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	CDC20B	psi-mi:“MI:0915”(physical association)	0.560
ALPP	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	CERCAM	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	KRTAP13-4	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	UFC1	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.560
NPPB	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	FBXL12	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	SPG21	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	KRTAP15-1	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	CCDC185	psi-mi:“MI:0915”(physical association)	0.560
USP2	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
GEMIN4	USP15	psi-mi:“MI:0915”(physical association)	0.560
CCT3	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
ZNF35	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (388): GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS), GEMIN4 (Affinity Capture-MS)

ESM2 similar proteins: A0JM49, A2AKG8, B0V0U5, B1AUR6, C5J7W8, E1BGH8, E1C231, E1C2Z0, E7FGT5, E7FH61, E9Q3L2, F6S215, O08662, O60287, O94822, P42356, P57678, P78527, P97313, Q13315, Q13535, Q14146, Q1RLU1, Q2TAW0, Q3TQQ9, Q3URQ0, Q571H0, Q5RDK1, Q5VW36, Q5WNI9, Q5XI94, Q5ZM41, Q62388, Q6A009, Q6DFV1, Q6PQD5, Q6ZRQ5, Q7SY48, Q86XI2, Q8BKX6

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FUS	“up-regulates activity”	GEMIN4	relocalization
GEMIN4	“form complex”	“SMN complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 163 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	7	36.4×	4e-08
snRNP Assembly	12	20.8×	2e-10
SARS-CoV-2 modulates host translation machinery	10	18.4×	2e-08
Ubiquitin-dependent degradation of Cyclin D	6	13.1×	3e-04
mRNA Splicing	14	12.6×	1e-09
RNA Polymerase II Transcription Termination	7	12.6×	9e-05
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	5	10.2×	4e-03
Processing of Capped Intron-Containing Pre-mRNA	15	10.1×	4e-09

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal snRNP assembly	13	52.8×	5e-17
spliceosomal complex assembly	6	25.2×	3e-05
U2-type prespliceosome assembly	5	21.8×	6e-04
positive regulation of fibroblast proliferation	6	12.4×	1e-03
mRNA splicing, via spliceosome	15	9.6×	3e-08
RNA splicing	15	9.2×	3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	247
Likely benign	52
Benign	23

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
147603	GRCh38/hg38 17p13.3(chr17:445331-823474)x3	Pathogenic
147604	GRCh38/hg38 17p13.3(chr17:333871-880361)x3	Pathogenic
1809605	NM_015721.3(GEMIN4):c.314C>T (p.Pro105Leu)	Pathogenic
3063481	GRCh37/hg19 17p13.3(chr17:141345-699175)x1	Pathogenic
4531677	NM_015721.3(GEMIN4):c.374_375del (p.Phe125fs)	Likely pathogenic

SpliceAI

387 predictions. Top by Δscore:

Variant	Effect	Δscore
17:752128:CCCA:C	donor_loss	0.9800
17:752129:CCA:C	donor_loss	0.9800
17:752130:CA:C	donor_loss	0.9800
17:752131:A:T	donor_loss	0.9800
17:752132:CCTAG:C	donor_loss	0.9800
17:752135:AGGT:A	donor_gain	0.9600
17:748033:C:CG	acceptor_loss	0.9500
17:748034:T:C	acceptor_loss	0.9500
17:748033:C:CC	acceptor_gain	0.9300
17:748035:G:C	acceptor_loss	0.9200
17:752127:ACCC:A	donor_loss	0.9100
17:748048:CCAAA:C	acceptor_loss	0.9000
17:751645:CTGTA:C	donor_loss	0.8900
17:751646:TGTA:T	donor_loss	0.8900
17:751647:GTA:G	donor_loss	0.8900
17:751648:TACCT:T	donor_loss	0.8900
17:751649:AC:A	donor_loss	0.8900
17:751650:CCTC:C	donor_loss	0.8900
17:751651:C:G	donor_loss	0.8900
17:751769:G:A	donor_gain	0.8800
17:752125:GCAC:G	donor_loss	0.8800
17:752126:CACC:C	donor_loss	0.8800
17:748049:CAAA:C	acceptor_loss	0.8700
17:751644:ACTGT:A	donor_loss	0.8600
17:752131:A:AC	donor_gain	0.8400
17:752132:C:CC	donor_gain	0.8400
17:751540:G:A	donor_gain	0.8200
17:751872:T:TA	donor_gain	0.8200
17:748040:C:CT	acceptor_gain	0.8100
17:751685:A:AC	donor_gain	0.8100

AlphaMissense

6936 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:745591:A:G	W818R	0.996
17:745591:A:T	W818R	0.996
17:745741:A:G	W768R	0.995
17:745741:A:T	W768R	0.995
17:747157:C:G	A296P	0.995
17:745493:G:C	S850R	0.994
17:745493:G:T	S850R	0.994
17:745495:T:G	S850R	0.994
17:745497:A:G	F849S	0.994
17:747553:A:G	W164R	0.994
17:747553:A:T	W164R	0.994
17:745389:A:T	L885H	0.993
17:745642:A:G	W801R	0.993
17:745642:A:T	W801R	0.993
17:747823:A:G	W74R	0.993
17:747823:A:T	W74R	0.993
17:745383:A:T	V887D	0.992
17:745438:A:G	W869R	0.991
17:745438:A:T	W869R	0.991
17:745485:A:G	F853S	0.991
17:745489:C:G	G852R	0.991
17:745491:T:A	K851I	0.990
17:745017:A:G	L1009P	0.989
17:745407:A:G	L879P	0.989
17:745496:G:C	F849L	0.989
17:745496:G:T	F849L	0.989
17:745498:A:G	F849L	0.989
17:745112:A:C	F977L	0.987
17:745112:A:T	F977L	0.987
17:745114:A:G	F977L	0.987

dbSNP variants (sampled 300 via entrez): RS1000006590 (17:754176 T>G), RS1000120687 (17:743980 A>T), RS1000183272 (17:748765 A>C), RS1000418146 (17:744053 G>C,T), RS1000466877 (17:749531 G>A), RS1000477423 (17:750780 G>A), RS1000490385 (17:750378 G>A), RS1000520736 (17:750538 T>C), RS1000625009 (17:755549 G>T), RS1000767642 (17:744258 C>T), RS1000803418 (17:750792 A>C), RS1001021211 (17:755912 A>G), RS1001070206 (17:745187 G>C), RS1001308240 (17:753048 A>G), RS1002504650 (17:747528 C>A,T)

Disease associations

OMIM: gene MIM:606969 | disease phenotypes: MIM:617913

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities	Strong	Autosomal recessive

Mondo (3): neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (MONDO:0060664), omphalocele (MONDO:0019015), microcephaly (MONDO:0001149)

Orphanet (1): Omphalocele (Orphanet:660)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000089	Renal hypoplasia
HP:0000121	Nephrocalcinosis
HP:0000126	Hydronephrosis
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000518	Cataract
HP:0000648	Optic atrophy
HP:0000822	Hypertension
HP:0000938	Osteopenia
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001265	Hyporeflexia
HP:0001344	Absent speech
HP:0001374	Congenital hip dislocation
HP:0001510	Growth delay
HP:0001744	Splenomegaly
HP:0001920	Renal artery stenosis
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002188	Delayed CNS myelination
HP:0002421	Poor head control
HP:0002540	Inability to walk
HP:0002656	Epiphyseal dysplasia
HP:0002783	Recurrent lower respiratory tract infections
HP:0002900	Hypokalemia
HP:0002901	Hypocalcemia
HP:0002902	Hyponatremia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001942_3	Prostate cancer	5.000000e-15

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169137 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3744741	GEMIN4		0.00	0

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
5.36	Kd	4352	nM	CHEMBL5653589
5.36	ED50	4352	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 3 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	2148425: Binding affinity to human GEMIN4 incubated for 45 mins by Kinobead based pull down assay	kd	4.3521	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Air Pollutants	decreases expression, increases abundance, affects response to substance, affects expression, affects reaction	4
Valproic Acid	affects expression, decreases expression, increases methylation	3
Soot	affects expression, affects response to substance, increases abundance	3
bisphenol A	decreases expression	2
cobaltous chloride	decreases expression	2
Formaldehyde	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	affects expression, affects response to substance, increases abundance, affects reaction	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
NSC 689534	decreases expression, affects binding	1
Rosiglitazone	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Pioglitazone	affects cotreatment, decreases expression	1
Troglitazone	decreases expression, decreases reaction	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5097601	Binding	Inhibition of p97 (unknown origin) expressed in Escherichia coli BL21 (DE3) preincubated for 10 mins followed by ATP addition measured for 30 to 120 mins by malachite green based assay	AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors. — Eur J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03520465	Not specified	UNKNOWN	Utility of a Supraaponeurotic Mesh as Prophylaxis of the Midline Eventration After an Oncological Colorrectal Resection
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT03765060	Not specified	UNKNOWN	The Efficacy and Security of the Small Stitch Technique in Emergency Surgery
NCT03960320	Not specified	COMPLETED	Health Related Quality of Life of Patients With Abdominal Wall Defects
NCT04126863	Not specified	COMPLETED	Omphaloceles and Associated Malformations
NCT04186039	Not specified	WITHDRAWN	Functional Evaluation of the Fetal Lung by Functional Magnetic Resonance Imaging - Blood Oxygenation Level Dependent (MRI-BOLD), in Congenital Diaphragmatic and Parietal Malformations
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT06014749	Not specified	COMPLETED	Serratus Intercostal Block Versus Epidural/Port Infiltration Analgesia in Eventration: Prospective Non Inferiority Study
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06731855	Not specified	RECRUITING	An Exploratory Physiological Study of Post-operative Recovery in Surgical Neonates and Dimethylarginine:Arginine Levels
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.