DRG1

Summary

DRG1 (developmentally regulated GTP binding protein 1, HGNC:3029) is a protein-coding gene on chromosome 22q12.2, encoding Developmentally-regulated GTP-binding protein 1 (Q9Y295). Catalyzes the conversion of GTP to GDP through hydrolysis of the gamma-phosphate bond in GTP. It is a selective cancer dependency (DepMap: 15.8% of cell lines).

Enables several functions, including GTPase activity; identical protein binding activity; and potassium ion binding activity. Involved in positive regulation of microtubule polymerization and regulation of mitotic spindle assembly. Located in cytosol and nuclear body.

Source: NCBI Gene 4733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tan-Almurshedi syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 33 total — 5 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 15.8% of screened cell lines
• MANE Select transcript: NM_004147

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3029
Approved symbol	DRG1
Name	developmentally regulated GTP binding protein 1
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000185721
Ensembl biotype	protein_coding
OMIM	603952
Entrez	4733

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000331457, ENST00000416465, ENST00000433341, ENST00000469673, ENST00000486584, ENST00000548143, ENST00000873504, ENST00000873505, ENST00000932029, ENST00000932030, ENST00000932031, ENST00000932032, ENST00000952387, ENST00000952388

RefSeq mRNA: 1 — MANE Select: NM_004147 NM_004147

CCDS: CCDS13897

Canonical transcript exons

ENST00000331457 — 9 exons

Exon	Start	End
ENSE00001291251	31423280	31423410
ENSE00001300082	31399604	31399725
ENSE00001307891	31426615	31426782
ENSE00001837700	31433872	31434452
ENSE00003540804	31420256	31420425
ENSE00003566607	31400620	31400743
ENSE00003580787	31411012	31411081
ENSE00003620615	31403029	31403204
ENSE00003641319	31427060	31427182

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8505 / max 864.2320, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191807	43.7929	1819
191806	2.0576	1133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.03	gold quality
right testis	UBERON:0004534	98.93	gold quality
adult organism	UBERON:0007023	98.66	gold quality
testis	UBERON:0000473	98.07	gold quality
male germ cell	CL:0000015	97.87	gold quality
triceps brachii	UBERON:0001509	97.78	gold quality
gluteal muscle	UBERON:0002000	97.76	gold quality
sperm	CL:0000019	97.74	gold quality
deltoid	UBERON:0001476	97.67	gold quality
tibialis anterior	UBERON:0001385	97.55	gold quality
quadriceps femoris	UBERON:0001377	97.46	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.46	gold quality
vastus lateralis	UBERON:0001379	97.42	gold quality
biceps brachii	UBERON:0001507	97.42	gold quality
skeletal muscle tissue	UBERON:0001134	97.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.10	gold quality
heart right ventricle	UBERON:0002080	97.08	gold quality
muscle tissue	UBERON:0002385	96.91	gold quality
muscle organ	UBERON:0001630	96.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.76	gold quality
gastrocnemius	UBERON:0001388	96.74	gold quality
muscle of leg	UBERON:0001383	96.60	gold quality
myocardium	UBERON:0002349	96.58	gold quality
islet of Langerhans	UBERON:0000006	96.39	gold quality
ganglionic eminence	UBERON:0004023	96.39	gold quality
diaphragm	UBERON:0001103	96.29	gold quality
type B pancreatic cell	CL:0000169	96.23	gold quality
ventricular zone	UBERON:0003053	96.15	gold quality
embryo	UBERON:0000922	96.00	gold quality
parotid gland	UBERON:0001831	95.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	28.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, SPI1

miRNA regulators (miRDB)

4 targeting DRG1, 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-4668-5P	99.79	70.58	3782
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-5002-3P	95.75	67.04	542

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 15.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Trx, dCBP, and Sbf1 are closely linked, physically and functionally, in the maintenance of Hox gene expression. (PMID:11701926)
• The Drosophila trithorax protein is a coactivator required to prevent re-establishment of polycomb silencing. (PMID:11973279)
• Genomic imprinting in Drosophila is maintained by the products of Suppressor of variegation and trithorax group, but not Polycomb group, genes. (PMID:12242505)
• Trithorax interacts with type 1 serine/threonine protein phosphatase. (PMID:12524522)
• This suggests that TRITHORAX bound to certain regulatory chromosome regions interacts with the adjacent elements of the nuclear scaffold, i.e., links the regions of actively transcribed genes with the nuclear matrix. (PMID:12669422)
• identified several members of the Polycomb and trithorax classes of genes required for the normal pattern of photoreceptor differentiation (PMID:15020417)
• Results suggest that protein phosphatase 1beta9C and Trithorax cooperate in Drosophila wing development. (PMID:15366010)
• Deletion analysis showed that the C-terminus of dDYRK2 modulated the interaction with SNR1 and TRX. (PMID:16671894)
• it is proposed that that the Trithorax complex, TAC1, promotes the mosaic pattern of Ubx expression by facilitating transcriptional elongation of bxd noncoding RNAs, which represses Ubx transcription (PMID:17174895)
• Data demonstrate that the Drosophila homologs of mixed-lineage leukemia protein and host cell factor 1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. (PMID:17698583)
• Computational analysis ofmicroarray data, identified 25 clusters of genes potentially regulated by TRX; most of these clusters consist of genes that encode structural proteins involved in cuticle formation. (PMID:18783608)
• results indicate that DNA binding proteins serve as platforms to assist PcG and trxG binding. Furthermore, several DNA sequence features discriminate between PcG- and TRX-N-bound regions (PMID:19143474)
• Hsp90 cooperates with Trx at chromatin for maintaining the active expression state of targets like the Hox genes. (PMID:19144915)
• These findings establish a role for PRC2 and TRX in the modulation of organismal longevity and stress resistance and indicate that moderate perturbation of Polycomb silencing can increase longevity. (PMID:20018689)
• Polycomb and trithorax control genome expression by determining the alternative epigenetic states of chromatin for key developmental regulators (PMID:21254568)
• dHCF possesses Enhancer of TrxG and PcG (ETP) properties. (PMID:22174740)
• Data imply that Trx, Pc, and E(z) remain bound or rapidly rebind to nascent DNA in the absence of trimethylated histones during DNA replication in Drosophila embryos. (PMID:22921915)
• mutations in PcG components and in TrxG members found in chromatin remodeling complexes enhance the gcm dominant phenotype, suggesting a balanced action of these chromatin modifiers regulate Gcm function (PMID:23300465)
• CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PMID:24743422)
• From the Drosophila melanogaster vestigial (vg) Polycomb response element/Trithorax response element switches the status of the element. (PMID:25108384)
• Trithorax maintains the functional heterogeneity of neural stem cells through the transcription factor buttonhead. (PMID:25285447)
• Trithorax has a role in regulating systemic signaling during Drosophila imaginal disc regeneration (PMID:26487779)
• If ASH1 or TRX function is lost or reduced, heterochromatin can spread into these domains creating a sink that diverts heterochromatic proteins from other variegating locations, which then may express a suppressed phenotype. (PMID:27373142)
• Trithorax positively regulates gene expression in Drosophila and co-occupies PREs to antagonize Polycomb-dependent silencing. Trx-dependent H3K4 dimethylation (H3K4me2) marks Drosophila PREs and maintains the developmental expression pattern of nearby genes. (PMID:27447986)
• Taken together, these data indicate that Atrophin is a major Trithorax-like cofactor that functions to moderate developmental gene transcription. (PMID:28327288)
• Mrg15 is a subunit of the Ash1 complex, a stimulator of Ash1 enzymatic activity and a critical regulator of the TrxG protein function of Ash1 in Drosophila. (PMID:29158494)
• Control of the gene activity by polycomb and trithorax group proteins in Drosophila (PMID:29372960)
• we demonstrate that the evolutionary conserved Lim3 core promoter provides basic Lim3 expression, whereas structural changes in the Lim3 PRE of distal promoter provide stage-, and tissue-specific Lim3 expression. Therefore, we hypothesize that PcG/TrxG proteins, which are directly involved in Lim3 transcription regulation, participate in lifespan control. (PMID:29555581)
• Trx and Grx have both, common and specific protein Cys redox targets and that down regulation of either redoxin has markedly different metabolic outcomes. They reflect the delicate sensitivity of redox equilibrium to changes in any of the elements involved and the difficulty of forecasting metabolic responses to redox environmental changes. (PMID:30639960)
• Trx, Ash1, and CBP proteins are required for the correct chromosome segregation and that Ash1 and CBP mediate for Cid/CENP-A recruitment at centromeres through post-translational histone modifications. (PMID:31203392)
• Dynamic Competition of Polycomb and Trithorax in Transcriptional Programming. (PMID:31928411)
• Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development. (PMID:38139143)
• Drg-1 is a candidate metastasis suppressor gene for prostate cancer and may serve as a useful prognostic marker. (PMID:12702552)
• our results strongly suggest functional involvement of the Drg-1 gene in suppressing the metastatic advancement of human breast cancer. (PMID:15184886)
• The tumor metastasis suppressor gene Drg-1 suppresses metastasis of prostate tumor cells by inhibiting the invasive ability of the cells via down-regulation of the expression of the ATF3 gene. (PMID:17178897)
• Lerepo4 action leaves Drg1 affinity for nucleotides unaffected, feasibly favoring a switch I reorientation, mainly via the TGS domain. (PMID:23711155)
• DRG-1 plays an important role in melanoma cell growth and transformation, indicating that DRG1 may represent a novel target for CD4(+) T cell-mediated immunotherapy in melanoma. (PMID:25993655)
• DRG1 was an important protein involved in spindle checkpoint signaling, and elevated levels of DRG1 caused lung adenocarcinoma and taxol resistance. (PMID:27626498)
• In vitro, DRG1 can diffuse on microtubules, promote their polymerization, drive microtubule formation into bundles, and stabilize microtubules. HeLa cells with reduced DRG1 levels show delayed progression from prophase to anaphase because spindle formation is slowed down. (PMID:28855639)
• m6A-dependent up-regulation of DRG1 by METTL3 and ELAVL1 promotes growth, migration, and colony formation in osteosarcoma. (PMID:32266933)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	drg1	ENSDARG00000039345
mus_musculus	Drg1	ENSMUSG00000020457
rattus_norvegicus	Drg1	ENSRNOG00000018590
drosophila_melanogaster	128up	FBGN0010339
caenorhabditis_elegans		WBGENE00012126

Paralogs (4): MTG2 (ENSG00000101181), GTPBP10 (ENSG00000105793), GTPBP4 (ENSG00000107937), DRG2 (ENSG00000108591)

Protein

Protein identifiers

Developmentally-regulated GTP-binding protein 1 — Q9Y295 (reviewed: Q9Y295)

Alternative names: Neural precursor cell expressed developmentally down-regulated protein 3, Translation factor GTPase DRG1

All UniProt accessions (3): Q9Y295, F8WEE0, H0YI06

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of GTP to GDP through hydrolysis of the gamma-phosphate bond in GTP. Appears to have an intrinsic GTPase activity that is stimulated by ZC3H15/DFRP1 binding likely by increasing the affinity for the potassium ions. When hydroxylated at C-3 of ‘Lys-22’ by JMJD7, may bind to RNA and play a role in translation. Binds to microtubules and promotes microtubule polymerization and stability that are required for mitotic spindle assembly during prophase to anaphase transition. GTPase activity is not necessary for these microtubule-related functions.

Subunit / interactions. Interacts (via its C-terminal) with TAL1. Interacts with DFRP1/ZC3H15; this interaction prevents DRG1 poly-ubiquitination and degradation by the proteasome. DRG1-ZC3H15/DFRP1 complex co-sediments with polysomes. Interacts with STK16. Interacts with JMJD7. Associates with microtubules either in an immobile or diffusive manner; in vitro binds to tubulin lacking the negatively charged C-terminal domain. (Microbial infection) Interacts with Chandipura virus matrix protein.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. High levels in skeletal muscle, heart, and kidney. Intermediate levels in liver, placenta and brain. Low levels in colon, thymus, spleen, small intestine, lung and leukocytes.

Post-translational modifications. Sumoylated by UBE2I in response to MEKK1-mediated stimuli. Phosphorylated at Thr-100 by STK16. Hydroxylated (with S stereochemistry) at C-3 of Lys-22 by JMJD7; this modification hinders trypsin-catalyzed proteolysis in vitro. Polyubiquitinated; this modification induces proteolytic degradation and is impaired by interaction with ZC3H15.

Disease relevance. Tan-Almurshedi syndrome (TANALS) [MIM:620641] An autosomal recessive neurodevelopmental disorder characterized by global developmental delay, intellectual deficit, poor or absent speech, failure to thrive, short stature, microcephaly, and craniofacial anomalies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The GTPase activity is enhanced by potassium ions as well as by DFRP1 binding.

Domain organisation. The ThrRS, GTPase, SpoT (TGS) domain is not necessary for GTP binding nor for the GTPase activity. It appears to play a regulatory role favoring GTP hydrolysis mediated by DFRP1/ZC3H15.

Induction. By androgens.

Similarity. Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family.

RefSeq proteins (1): NP_004138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004095	TGS	Domain
IPR005225	Small_GTP-bd	Domain
IPR006073	GTP-bd	Domain
IPR006074	GTP1-OBG_CS	Conserved_site
IPR012675	Beta-grasp_dom_sf	Homologous_superfamily
IPR012676	TGS-like	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031167	G_OBG	Domain
IPR031662	GTP-binding_2	Domain
IPR045001	DRG	Family

Pfam: PF01926, PF02824, PF16897

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (30 total): strand 7, binding site 5, sequence variant 4, modified residue 3, mutagenesis site 3, domain 2, initiator methionine 1, chain 1, sequence conflict 1, helix 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2EKI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y295-F1	84.76	0.50

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 (5): 71–78; 78; 98; 117–121; 248–251

Post-translational modifications (3): 2, 22, 100

Mutagenesis-validated functional residues (3):

Position	Phenotype
22	impairs jmjd7-mediated hydroxylation.
100	reduces the gtpase activity.
117	loss of gtpase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9629569	Protein hydroxylation

MSigDB gene sets: 309 (showing top): MORF_MTA1, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, MORF_UBE2I, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MORF_HDAC1, MORF_RAD21, MORF_HDAC2, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, MORF_PSMC2, CAGCTG_AP4_Q5, GOBP_TRANSLATION

GO Biological Process (3): cytoplasmic translation (GO:0002181), positive regulation of microtubule polymerization (GO:0031116), regulation of mitotic spindle assembly (GO:1901673)

GO Molecular Function (9): GTPase activity (GO:0003924), GTP binding (GO:0005525), microtubule binding (GO:0008017), potassium ion binding (GO:0030955), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
translation	1
positive regulation of microtubule polymerization or depolymerization	1
regulation of microtubule polymerization	1
positive regulation of protein polymerization	1
microtubule polymerization	1
positive regulation of supramolecular fiber organization	1
regulation of mitotic spindle organization	1
regulation of spindle assembly	1
mitotic spindle assembly	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
tubulin binding	1
alkali metal ion binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2964 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DRG1	ZC3H15	Q8WU90	735
DRG1	RWDD1	Q9H446	715
DRG1	KNOP1	Q1ED39	533
DRG1	STK16	O75716	526
DRG1	C10orf62	Q5T681	479
DRG1	TUBD1	Q9UJT1	458
DRG1	CFAP141	Q5VU69	435
DRG1	ARMCX6	Q7L4S7	415
DRG1	PASK	Q96RG2	402
DRG1	OR5M3	Q8NGP4	396
DRG1	ZNF285	Q96NJ3	371
DRG1	TRAPPC6B	Q86SZ2	356
DRG1	XAGE5	Q8WWM1	354
DRG1	CCDC47	Q96A33	325
DRG1	NIBAN3	Q86XR2	299

IntAct

155 interactions, top by confidence:

A	B	Type	Score
DRG1	ZC3H15	psi-mi:“MI:0915”(physical association)	0.930
ZC3H15	DRG1	psi-mi:“MI:0915”(physical association)	0.930
DRG1	RWDD1	psi-mi:“MI:0915”(physical association)	0.800
RWDD1	DRG1	psi-mi:“MI:0915”(physical association)	0.800
ARX1	RPL25	psi-mi:“MI:0914”(association)	0.770
BUD20	RSA4	psi-mi:“MI:0914”(association)	0.730
PKMYT1	CCNB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PHC2	DRG1	psi-mi:“MI:0915”(physical association)	0.670
DRG1	PHC2	psi-mi:“MI:0915”(physical association)	0.670
DRG1	CFTR	psi-mi:“MI:0915”(physical association)	0.640
M	DRG1	psi-mi:“MI:0915”(physical association)	0.580
DRG1	STK16	psi-mi:“MI:0915”(physical association)	0.560
SKIL	DRG1	psi-mi:“MI:0915”(physical association)	0.560
DRG1	COIL	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (464): DRG1 (Two-hybrid), SKIL (Two-hybrid), COIL (Two-hybrid), STK16 (Two-hybrid), RWDD1 (Two-hybrid), ZC3H15 (Two-hybrid), SSX2IP (Two-hybrid), DRG1 (Affinity Capture-MS), DRG1 (Affinity Capture-MS), DRG1 (Affinity Capture-MS), DRG1 (Affinity Capture-MS), LRRC41 (Affinity Capture-MS), ZC3H15 (Affinity Capture-MS), NTMT1 (Affinity Capture-MS), HAO1 (Affinity Capture-MS)

ESM2 similar proteins: A0B555, A0B9V5, A1RWW7, A2SSM7, A3DMP2, A3DNC2, A4FWF9, A4IJK2, A6UV53, A6VGU6, A9A458, A9A9V3, B1Y8V5, B4U514, B6YSM9, B6YT14, B8E1E7, B9DSW4, C0MAG4, C0MCC4, C5A270, C6A175, C6A1F8, O27122, O28394, O59432, O74019, P31815, P32233, P41559, P54041, P56209, P61519, Q12WS3, Q2NEK1, Q2RFR1, Q3MHP5, Q464Y4, Q58443, Q5JE31

Diamond homologs: A1TYY4, A4GAN2, A6LD68, A6Q4D2, A7I166, A8MH56, B0B7Y8, B0BC53, B2S3Y1, B2USD4, B5EJF7, B5ZA69, B6YRA6, B7IGK8, B7JC34, B9K736, G0S8F1, O44411, O67849, O83724, O84423, O94659, P0C8N9, P0C8P1, P17103, P32233, P32234, P43690, P53295, Q02892, Q07UP2, Q07YJ0, Q0ATU5, Q0SM73, Q17Y93, Q1GSF4, Q253F8, Q2QZ37, Q30QP0, Q39QR4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
STK16	unknown	DRG1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 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
Downstream signal transduction	5	19.4×	3e-04
Negative regulation of MAPK pathway	5	13.6×	8e-04
Signaling by BRAF and RAF1 fusions	6	10.4×	6e-04
Regulation of RAS by GAPs	5	9.9×	3e-03
Eukaryotic Translation Termination	8	9.8×	2e-04
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	8	9.6×	2e-04
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	8	9.6×	2e-04
SRP-dependent cotranslational protein targeting to membrane	9	9.2×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	11	17.1×	5e-08
translation	11	9.5×	1e-05
regulation of cell cycle	9	5.6×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	5
Uncertain significance	21
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2664492	NM_004147.4(DRG1):c.160G>T (p.Gly54Ter)	Likely pathogenic
2664493	NM_004147.4(DRG1):c.742_743inv (p.Asn248Phe)	Likely pathogenic
2664494	NM_004147.4(DRG1):c.787A>T (p.Lys263Ter)	Likely pathogenic
2664495	NM_004147.4(DRG1):c.418C>T (p.Arg140Ter)	Likely pathogenic
816815	NM_004147.4(DRG1):c.118C>T (p.Arg40Ter)	Likely pathogenic

SpliceAI

5190 predictions. Top by Δscore:

Variant	Effect	Δscore
22:31400614:TTTTA:T	acceptor_loss	1.0000
22:31400615:TTTAG:T	acceptor_loss	1.0000
22:31400616:TTA:T	acceptor_loss	1.0000
22:31400617:TA:T	acceptor_loss	1.0000
22:31400618:A:AG	acceptor_gain	1.0000
22:31400618:AGATG:A	acceptor_gain	1.0000
22:31400619:G:GG	acceptor_gain	1.0000
22:31400619:GAT:G	acceptor_gain	1.0000
22:31400619:GATGG:G	acceptor_gain	1.0000
22:31400742:AG:A	donor_loss	1.0000
22:31400743:GGTT:G	donor_loss	1.0000
22:31400744:G:GA	donor_loss	1.0000
22:31400745:T:A	donor_loss	1.0000
22:31403202:CAGGT:C	donor_loss	1.0000
22:31403203:AGGTG:A	donor_loss	1.0000
22:31403205:GTG:G	donor_loss	1.0000
22:31403206:T:A	donor_loss	1.0000
22:31410996:A:AG	acceptor_gain	1.0000
22:31410997:T:G	acceptor_gain	1.0000
22:31411002:A:AG	acceptor_gain	1.0000
22:31411009:CA:C	acceptor_loss	1.0000
22:31411010:A:AG	acceptor_gain	1.0000
22:31411011:G:GA	acceptor_gain	1.0000
22:31411011:GCTC:G	acceptor_gain	1.0000
22:31411011:GCTCC:G	acceptor_gain	1.0000
22:31420247:A:AG	acceptor_gain	1.0000
22:31420248:C:G	acceptor_gain	1.0000
22:31420250:CTTCA:C	acceptor_loss	1.0000
22:31420251:TTCAG:T	acceptor_loss	1.0000
22:31420252:TCAG:T	acceptor_loss	1.0000

AlphaMissense

2399 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:31400656:C:G	H27D	1.000
22:31400669:T:C	L31P	1.000
22:31400690:T:C	L38P	1.000
22:31403031:T:C	F57L	1.000
22:31403033:T:A	F57L	1.000
22:31403033:T:G	F57L	1.000
22:31403065:G:A	G68E	1.000
22:31403073:G:C	G71R	1.000
22:31403074:G:A	G71D	1.000
22:31403080:C:A	P73Q	1.000
22:31403088:G:A	G76R	1.000
22:31403088:G:C	G76R	1.000
22:31403088:G:T	G76W	1.000
22:31403089:G:A	G76E	1.000
22:31403089:G:T	G76V	1.000
22:31403091:A:C	K77Q	1.000
22:31403092:A:T	K77M	1.000
22:31403093:G:C	K77N	1.000
22:31403093:G:T	K77N	1.000
22:31403094:T:C	S78P	1.000
22:31403095:C:T	S78L	1.000
22:31403148:T:A	F96I	1.000
22:31403148:T:C	F96L	1.000
22:31403148:T:G	F96V	1.000
22:31403149:T:C	F96S	1.000
22:31403149:T:G	F96C	1.000
22:31403150:C:A	F96L	1.000
22:31403150:C:G	F96L	1.000
22:31403152:C:T	T97I	1.000
22:31403155:C:T	T98I	1.000

dbSNP variants (sampled 300 via entrez): RS1000034017 (22:31408787 T>C), RS1000091695 (22:31403424 T>G), RS1000103572 (22:31398661 A>G), RS1000106008 (22:31432818 C>T), RS1000114874 (22:31399166 C>T), RS1000130867 (22:31409406 C>A), RS1000134227 (22:31412141 A>C), RS1000137265 (22:31421743 G>T), RS1000187099 (22:31412625 A>G), RS1000532243 (22:31425646 G>A), RS1000649259 (22:31402462 C>G), RS1000649504 (22:31421599 C>T), RS1000696801 (22:31409772 T>C), RS1000703195 (22:31405313 G>A,T), RS1000738711 (22:31415521 G>C)

Disease associations

OMIM: gene MIM:603952 | disease phenotypes: MIM:620641

GenCC curated gene-disease

Disease	Classification	Inheritance
Tan-Almurshedi syndrome	Strong	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (3): Tan-Almurshedi syndrome (MONDO:0957990), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004620_133	Sum basophil neutrophil counts	5.000000e-09
GCST004629_52	Neutrophil count	8.000000e-09
GCST010135_20	Oily fish consumption	3.000000e-10
GCST010135_5	Oily fish consumption	1.000000e-15
GCST010140_12	Pork consumption	3.000000e-10
GCST010140_49	Pork consumption	1.000000e-15
GCST010142_11	Fish- and plant-related diet	1.000000e-11
GCST010142_79	Fish- and plant-related diet	3.000000e-08
GCST010653_5	Thyroid stimulating hormone levels	4.000000e-08
GCST90002398_27	Neutrophil count	6.000000e-17

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0005090	basophil count
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066214 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.75	IC50	180	nM	CHEMBL3393328
5.85	Kd	1413	nM	CHEMBL5653589
5.83	ED50	1472	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 3 total; 2 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
2-[[4-(1-acetylpiperidin-4-yl)-6-(3,3-difluoropyrrolidin-1-yl)-2-pyridinyl]amino]pyridine-4-carbonitrile	2141505: Inhibition of DRG1 (unknown origin)	ic50	0.1800	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148264: Binding affinity to human DRG1 incubated for 45 mins by Kinobead based pull down assay	kd	1.4134	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, decreases expression, affects expression	2
GSK-J4	increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
selenomethylselenocysteine	affects cotreatment, decreases expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
sodium arsenite	affects binding, decreases reaction, decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Irinotecan	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	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
CHEMBL5635903	Binding	Inhibition of DRG1 (unknown origin)	Applications of oxetanes in drug discovery and medicinal chemistry. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2W2	Abcam HEK293T DRG1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism