GDI1

Summary

GDI1 (GDP dissociation inhibitor 1, HGNC:4226) is a protein-coding gene on chromosome Xq28, encoding Rab GDP dissociation inhibitor alpha (P31150). Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them.

GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. GDIs slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs. GDI1 is expressed primarily in neural and sensory tissues. Mutations in GDI1 have been linked to X-linked nonspecific cognitive disability.

Source: NCBI Gene 2664 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, X-linked 41 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 250 total — 8 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001493

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4226
Approved symbol	GDI1
Name	GDP dissociation inhibitor 1
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	RABGDIA, XAP-4, OPHN2, FLJ41411
Ensembl gene	ENSG00000203879
Ensembl biotype	protein_coding
OMIM	300104
Entrez	2664

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 11 protein_coding, 6 retained_intron, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000415109, ENST00000434049, ENST00000445564, ENST00000447750, ENST00000460984, ENST00000465640, ENST00000468483, ENST00000471972, ENST00000475976, ENST00000476540, ENST00000481304, ENST00000485143, ENST00000489589, ENST00000491154, ENST00000630693, ENST00000905223, ENST00000905224, ENST00000905225, ENST00000905226, ENST00000929658, ENST00000929659, ENST00000929660, ENST00000963418, ENST00000963419

RefSeq mRNA: 1 — MANE Select: NM_001493 NM_001493

CCDS: CCDS35452

Canonical transcript exons

ENST00000447750 — 11 exons

Exon	Start	End
ENSE00001450790	154440375	154440506
ENSE00001450794	154439941	154440139
ENSE00001944749	154442520	154443467
ENSE00003526100	154438523	154438630
ENSE00003588926	154437154	154437299
ENSE00003615917	154441096	154441195
ENSE00003626722	154439006	154439140
ENSE00003645854	154438765	154438864
ENSE00003662111	154441623	154441794
ENSE00003662269	154442374	154442428
ENSE00003670086	154442111	154442255

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.8874 / max 1004.7530, expressed in 1827 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198167	39.1427	1813
198168	11.4046	1728
198165	9.6792	1782
198164	3.4008	1556
198183	1.6227	834
198169	1.6085	700
198179	1.4002	732
198182	1.0758	594
198178	0.9575	490
198172	0.9491	560

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.71	gold quality
cerebellar cortex	UBERON:0002129	99.66	gold quality
cerebellar hemisphere	UBERON:0002245	99.66	gold quality
right frontal lobe	UBERON:0002810	99.63	gold quality
prefrontal cortex	UBERON:0000451	99.58	gold quality
cortical plate	UBERON:0005343	99.55	gold quality
cerebellum	UBERON:0002037	99.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.49	gold quality
frontal cortex	UBERON:0001870	99.48	gold quality
ganglionic eminence	UBERON:0004023	99.47	gold quality
cingulate cortex	UBERON:0003027	99.45	gold quality
anterior cingulate cortex	UBERON:0009835	99.44	gold quality
neocortex	UBERON:0001950	99.43	gold quality
parietal lobe	UBERON:0001872	99.42	gold quality
postcentral gyrus	UBERON:0002581	99.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.38	gold quality
nucleus accumbens	UBERON:0001882	99.34	gold quality
hypothalamus	UBERON:0001898	99.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.33	gold quality
cerebral cortex	UBERON:0000956	99.32	gold quality
amygdala	UBERON:0001876	99.32	gold quality
spinal cord	UBERON:0002240	99.30	gold quality
telencephalon	UBERON:0001893	99.28	gold quality
adenohypophysis	UBERON:0002196	99.27	gold quality
forebrain	UBERON:0001890	99.26	gold quality
ventral tegmental area	UBERON:0002691	99.26	gold quality
brain	UBERON:0000955	99.25	gold quality
central nervous system	UBERON:0001017	99.25	gold quality
caudate nucleus	UBERON:0001873	99.23	gold quality
pituitary gland	UBERON:0000007	99.22	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	44.80
E-ANND-3	yes	9.04
E-MTAB-2983	no	362.85
E-MTAB-9543	no	2.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

77 targeting GDI1, 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-188-3P	100.00	68.76	1240
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6779-5P	99.70	65.76	2363

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• RhoGDI has a role in inactivating Rho GTPases with ExoS RhoGAP (PMID:15292224)
• isoprenylcysteine carboxylmethyltransferase regulates Rac1 activity by controlling the interaction of Rac1 with RhoGDI through TNFA (PMID:15647276)
• RhoGDI overexpression is associated with paclitaxel resistance in ovarian cancers (PMID:16596196)
• The results of case-control analysis indicated that, no association between the rs11549300 polymorphisms of GDI1 and children NSMR (P >0.05), but its polymorphisms may be related to intelligence levels of children in Qinba region (P =0.03). (PMID:18487148)
• GDI-1 is preferentially involved in insulin-stimulated glucose transporter 4 (GLUT4) translocation through facilitating Rab10 recycling. (PMID:19570034)
• A model by which mutant PrP induces overexpression of GDI, activating a cytotoxic feedback loop that leads to protein accumulation in the secretory pathway. (PMID:19996123)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• The mutations in this gene are common and do not seem to influence the gene expression so as to cause a change in phenotype. (PMID:21736009)
• GDI1 mutations cause an unspecific phenotype characterized by cognitive deficits of variable degree in males, and to a lesser degree in female carriers. (PMID:22002931)
• The results of this study identified RabGDI as a component of the switching mechanism that is required for commissural axons to change their response from attraction to repulsion at the intermediate target (PMID:23140504)
• Data confirm isolated adrenocorticotropin deficiency (IAD) as autoimmune disease; RABGDIA (human, human recombinant, or rat) exhibits characteristics of autoantigen in anterior pituitary; patients with IAD exhibit autoantibodies against RABGDIA. (PMID:25346144)
• Human oligodendrogliomas cells stably expressing mutant GDI1 showed altered cell proliferation. (PMID:25694352)
• The interplay of Rac1 activity, ubiquitination and GDI binding and its consequences for endothelial cell spreading. (PMID:34252134)
• Overexpression of GDP dissociation inhibitor 1 gene associates with the invasiveness and poor outcomes of colorectal cancer. (PMID:34515625)
• GDP dissociation inhibitor 1 (GDI1) attenuates beta-amyloid-induced neurotoxicity in Alzheimer’s diseases. (PMID:38013121)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gdi1	ENSDARG00000056122
mus_musculus	Gdi1	ENSMUSG00000015291
rattus_norvegicus	Gdi1	ENSRNOG00000056870
drosophila_melanogaster	Gdi	FBGN0004868
caenorhabditis_elegans		WBGENE00001558

Paralogs (3): GDI2 (ENSG00000057608), CHM (ENSG00000188419), CHML (ENSG00000203668)

Protein

Protein identifiers

Rab GDP dissociation inhibitor alpha — P31150 (reviewed: P31150)

Alternative names: Guanosine diphosphate dissociation inhibitor 1, Oligophrenin-2, Protein XAP-4

All UniProt accessions (5): A0A0S2Z3X8, P31150, F8WCU0, F8WE59, G5E9U5

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Promotes the dissociation of GDP-bound Rab proteins from the membrane and inhibits their activation. Promotes the dissociation of RAB1A, RAB3A, RAB5A and RAB10 from membranes.

Subunit / interactions. Interacts with RHOH. Interacts with the non-phosphorylated forms of RAB1A, RAB3A, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43.

Subcellular location. Cytoplasm. Golgi apparatus. trans-Golgi network.

Tissue specificity. Brain; predominant in neural and sensory tissues.

Disease relevance. Intellectual developmental disorder, X-linked 41 (XLID41) [MIM:300849] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Rab GDI family.

RefSeq proteins (1): NP_001484* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000806	RabGDI	Family
IPR018203	GDP_dissociation_inhibitor	Family
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily

Pfam: PF00996

UniProt features (10 total): sequence conflict 7, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31150-F1	93.32	0.87

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 298 (showing top): GNF2_RTN1, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, REACTOME_MEMBRANE_TRAFFICKING, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_PROTEIN_TARGETING_TO_MEMBRANE

GO Biological Process (14): signal transduction (GO:0007165), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), Rab protein signal transduction (GO:0032482), positive regulation of toll-like receptor signaling pathway (GO:0034123), positive regulation of axon extension (GO:0045773), negative regulation of axonogenesis (GO:0050771), response to calcium ion (GO:0051592), negative regulation of protein targeting to membrane (GO:0090315), negative regulation of protein localization (GO:1903828), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), Golgi to plasma membrane transport (GO:0006893), small GTPase-mediated signal transduction (GO:0007264), toll-like receptor 4 signaling pathway (GO:0034142)

GO Molecular Function (5): GDP-dissociation inhibitor activity (GO:0005092), Rab GDP-dissociation inhibitor activity (GO:0005093), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), axon (GO:0030424), midbody (GO:0030496), protein-containing complex (GO:0032991), neuronal cell body (GO:0043025), myelin sheath (GO:0043209), presynaptic cytosol (GO:0099523)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	4
cellular process	2
transport	2
intracellular protein localization	2
GTPase regulator activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
establishment of protein localization	1
small GTPase-mediated signal transduction	1
toll-like receptor signaling pathway	1
regulation of toll-like receptor signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
axonogenesis	1
negative regulation of neuron projection development	1
negative regulation of neurogenesis	1
regulation of axonogenesis	1
response to metal ion	1
protein targeting to membrane	1
negative regulation of cellular process	1
regulation of protein targeting to membrane	1
negative regulation of establishment of protein localization	1
regulation of protein localization	1
negative regulation of biological process	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
post-Golgi vesicle-mediated transport	1
vesicle-mediated transport to the plasma membrane	1
intracellular signaling cassette	1
cell surface toll-like receptor signaling pathway	1

Protein interactions and networks

STRING

1914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDI1	RAB39B	Q96DA2	874
GDI1	AGFG1	P52594	858
GDI1	ATP6AP1	Q15904	834
GDI1	RAB1A	P11476	816
GDI1	RAB3A	P20336	801
GDI1	MECP2	P51608	739
GDI1	GPM6B	Q13491	691
GDI1	RAB8A	P24407	669
GDI1	NTNG2	Q96CW9	648
GDI1	RAB10	P61026	647
GDI1	GLUD2	P49448	643
GDI1	NTNG1	Q9Y2I2	639
GDI1	NSF	P46459	614
GDI1	GLRA2	P23416	592
GDI1	CDKL5	O76039	587

IntAct

135 interactions, top by confidence:

A	B	Type	Score
RAB8A	GDI1	psi-mi:“MI:0914”(association)	0.860
GDI1	RAB4A	psi-mi:“MI:0914”(association)	0.820
GDI1	RAB4A	psi-mi:“MI:0915”(physical association)	0.820
GDI1	RAB4A	psi-mi:“MI:2364”(proximity)	0.820
RAB1A	GDI1	psi-mi:“MI:0915”(physical association)	0.800
RAB12	GDI1	psi-mi:“MI:0914”(association)	0.790
RAB10	GDI1	psi-mi:“MI:0914”(association)	0.790
RAB5A	GDI1	psi-mi:“MI:0914”(association)	0.730
RAB6B	GDI1	psi-mi:“MI:0914”(association)	0.730
RAB9A	GDI1	psi-mi:“MI:0914”(association)	0.730
GDI1	LNX1	psi-mi:“MI:0915”(physical association)	0.720
LNX1	GDI1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
GOLM1	EGFR	psi-mi:“MI:0914”(association)	0.640
RAB31	CHM	psi-mi:“MI:0914”(association)	0.640
RAB32	CHM	psi-mi:“MI:0914”(association)	0.640
RAB8B	GDI1	psi-mi:“MI:0914”(association)	0.640
RAB9A	CHM	psi-mi:“MI:0914”(association)	0.610

BioGRID (282): LNX1 (Two-hybrid), GDI1 (Affinity Capture-MS), GDI1 (Affinity Capture-RNA), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), GDI1 (Co-fractionation), MSN (Co-fractionation), TAGLN2 (Co-fractionation), GDI1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K9RL25, A0A0U1WZ18, A0A1S4A695, B9N1F9, O15305, O35621, O80840, O88958, O97555, O97556, P21856, P31150, P46926, P50396, P50398, P50399, P60028, P78330, Q16HW7, Q1W374, Q1W375, Q1W376, Q1W377, Q259G4, Q2KHU0, Q3SZJ9, Q3UFY7, Q4R7R3, Q5E982, Q5R8T8, Q5RB83, Q5ZID6, Q5ZKF6, Q60HD6, Q61598, Q64422, Q6AYP7, Q6Q7J2, Q7SYN4, Q7XPW5

Diamond homologs: G4MT60, O24653, O97555, O97556, P21856, P31150, P39958, P50395, P50396, P50397, P50398, P50399, P60028, Q10305, Q5RCE1, Q61598, Q6Q7J2, Q7YQM0, Q8HXX7, Q96254, Q9LXC0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 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
RAB geranylgeranylation	30	56.4×	2e-44
TBC/RABGAPs	12	33.9×	1e-13
RAB GEFs exchange GTP for GDP on RABs	23	31.0×	2e-26
Translocation of SLC2A4 (GLUT4) to the plasma membrane	8	13.4×	2e-05
Neutrophil degranulation	16	4.0×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
antigen processing and presentation	8	53.0×	6e-10
Rab protein signal transduction	5	46.8×	6e-06
regulated exocytosis	5	41.8×	8e-06
autophagosome assembly	10	21.2×	1e-08
endocytic recycling	7	17.7×	1e-05
exocytosis	10	14.3×	3e-07
endoplasmic reticulum to Golgi vesicle-mediated transport	9	11.5×	8e-06
endosomal transport	5	11.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	7
Uncertain significance	82
Likely benign	28
Benign	6

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
11627	NM_001493.3(GDI1):c.208C>T (p.Arg70Ter)	Pathogenic
11628	NM_001493.3(GDI1):c.1268G>C (p.Arg423Pro)	Pathogenic
29933	NM_001493.3(GDI1):c.1186_1187del (p.Ser396fs)	Pathogenic
3237495	NM_001493.3(GDI1):c.1088_1089insT (p.Glu363fs)	Pathogenic
3853342	NM_001493.3(GDI1):c.442del (p.Ala148fs)	Pathogenic
565269	GRCh37/hg19 Xq28(chrX:153560741-153761134)x2	Pathogenic
975399	NM_001493.3(GDI1):c.1060_1064del (p.Ser354fs)	Pathogenic
976430	NM_001493.3(GDI1):c.1173_1174insACATGAT (p.Asp392delinsThrTer)	Pathogenic
1333612	NM_001493.3(GDI1):c.45+1G>A	Likely pathogenic
1683290	NM_001493.3(GDI1):c.706C>T (p.Gln236Ter)	Likely pathogenic
1705314	NM_001493.3(GDI1):c.706del (p.Gln236fs)	Likely pathogenic
3340705	NM_001493.3(GDI1):c.1267C>T (p.Arg423Cys)	Likely pathogenic
431932	NM_001493.3(GDI1):c.473T>C (p.Phe158Ser)	Likely pathogenic
521670	NM_001493.3(GDI1):c.819+1G>A	Likely pathogenic
976035	NM_001493.3(GDI1):c.788del (p.Gly263fs)	Likely pathogenic

SpliceAI

2093 predictions. Top by Δscore:

Variant	Effect	Δscore
X:154437300:G:GG	donor_gain	1.0000
X:154438627:GGAG:G	donor_gain	1.0000
X:154438628:GAGG:G	donor_gain	1.0000
X:154438629:AGG:A	donor_loss	1.0000
X:154438631:G:GA	donor_loss	1.0000
X:154438632:T:G	donor_loss	1.0000
X:154438763:A:AG	acceptor_gain	1.0000
X:154438764:G:GG	acceptor_gain	1.0000
X:154438764:GCT:G	acceptor_gain	1.0000
X:154438764:GCTGT:G	acceptor_gain	1.0000
X:154438876:G:GT	donor_gain	1.0000
X:154438880:G:GT	donor_gain	1.0000
X:154439000:CCACA:C	acceptor_loss	1.0000
X:154439003:CA:C	acceptor_loss	1.0000
X:154439004:A:AG	acceptor_gain	1.0000
X:154439004:AG:A	acceptor_gain	1.0000
X:154439004:AGG:A	acceptor_gain	1.0000
X:154439005:G:GT	acceptor_gain	1.0000
X:154439005:GG:G	acceptor_gain	1.0000
X:154439005:GGG:G	acceptor_gain	1.0000
X:154439005:GGGCA:G	acceptor_gain	1.0000
X:154439136:TTCCA:T	donor_gain	1.0000
X:154439137:TCCA:T	donor_gain	1.0000
X:154439139:CA:C	donor_gain	1.0000
X:154439141:G:GG	donor_gain	1.0000
X:154439929:C:A	acceptor_gain	1.0000
X:154439936:CTTAG:C	acceptor_loss	1.0000
X:154439937:TTAG:T	acceptor_loss	1.0000
X:154439938:TAG:T	acceptor_loss	1.0000
X:154439939:A:AG	acceptor_gain	1.0000

AlphaMissense

2970 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:154437285:G:A	G11R	1.000
X:154437285:G:C	G11R	1.000
X:154437285:G:T	G11W	1.000
X:154437286:G:A	G11E	1.000
X:154438539:G:A	G21D	1.000
X:154438569:T:C	L31P	1.000
X:154438592:T:C	Y39H	1.000
X:154438596:G:A	G40E	1.000
X:154438825:T:A	W72R	1.000
X:154438825:T:C	W72R	1.000
X:154438832:T:A	V74D	1.000
X:154438834:G:C	D75H	1.000
X:154438835:A:T	D75V	1.000
X:154439024:T:C	L91P	1.000
X:154439056:T:C	F102L	1.000
X:154439058:C:A	F102L	1.000
X:154439058:C:G	F102L	1.000
X:154439074:A:C	S108R	1.000
X:154439076:C:A	S108R	1.000
X:154439076:C:G	S108R	1.000
X:154439111:C:A	P120Q	1.000
X:154439129:C:A	A126D	1.000
X:154439963:A:C	K137N	1.000
X:154439963:A:T	K137N	1.000
X:154440109:G:A	G186D	1.000
X:154440430:T:C	S215P	1.000
X:154440451:A:C	S222R	1.000
X:154440453:C:A	S222R	1.000
X:154440453:C:G	S222R	1.000
X:154440475:G:C	G230R	1.000

dbSNP variants (sampled 300 via entrez): RS1001589429 (X:154435851 A>G), RS1001620566 (X:154436280 G>A), RS1002151814 (X:154443837 T>G), RS1004059788 (X:154442946 A>G), RS1004946806 (X:154436615 C>A), RS1007401464 (X:154439487 C>T), RS1008053761 (X:154443720 C>G,T), RS1008689429 (X:154443333 C>A,T), RS1009081584 (X:154437579 A>G,T), RS1010175832 (X:154438004 T>A,G), RS1010600120 (X:154442051 C>A,T), RS1011581229 (X:154443412 C>T), RS1011612349 (X:154443781 G>T), RS1012080406 (X:154435235 C>T), RS1013927261 (X:154438114 C>T)

Disease associations

OMIM: gene MIM:300104 | disease phenotypes: MIM:300849, MIM:300972

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 41	Strong	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Moderate	XL

Mondo (4): intellectual disability, X-linked 41 (MONDO:0010451), immunodeficiency 47 (MONDO:0010504), intellectual disability (MONDO:0001071), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (3): X-linked non-syndromic intellectual disability (Orphanet:777), ATP6AP1-CDG (Orphanet:692790), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001417	X-linked inheritance
HP:0001423	X-linked dominant inheritance
HP:0002121	Generalized non-motor (absence) seizure
HP:0008936	Axial hypotonia
HP:0010864	Severe intellectual disability

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066920 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.50	Kd	3126	nM	CHEMBL5653589
5.39	ED50	4054	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2148423: Binding affinity to human GDI1 incubated for 45 mins by Kinobead based pull down assay	kd	3.1258	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	3
sodium arsenite	affects cotreatment, increases expression	3
Smoke	decreases expression	2
Cadmium Chloride	increases expression	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
potassium chromate(VI)	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	affects expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carmustine	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Quercetin	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651465	Binding	Binding affinity to human GDI1 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)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders