ARHGAP4

Summary

ARHGAP4 (Rho GTPase activating protein 4, HGNC:674) is a protein-coding gene on chromosome Xq28, encoding Rho GTPase-activating protein 4 (P98171). Inhibitory effect on stress fiber organization.

This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins belonging to the RAS superfamily. The protein encoded by the orthologous gene in rat is localized to the Golgi complex and can redistribute to microtubules. The rat protein stimulates the activity of some Rho GTPases in vitro. Genomic deletions of this gene and a neighboring gene have been found in patients with nephrogenic diabetes insipidus. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 393 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 286 total — 27 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001666

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:674
Approved symbol	ARHGAP4
Name	Rho GTPase activating protein 4
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0131, C1, p115, RhoGAP4, SrGAP4
Ensembl gene	ENSG00000089820
Ensembl biotype	protein_coding
OMIM	300023
Entrez	393

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 18 protein_coding, 8 retained_intron, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000350060, ENST00000370016, ENST00000370028, ENST00000393721, ENST00000404127, ENST00000418750, ENST00000420383, ENST00000422091, ENST00000422918, ENST00000442172, ENST00000442262, ENST00000454164, ENST00000460782, ENST00000461052, ENST00000461739, ENST00000463905, ENST00000466928, ENST00000467421, ENST00000470209, ENST00000470979, ENST00000488269, ENST00000494302, ENST00000494397, ENST00000494813, ENST00000700282, ENST00000907988, ENST00000907989, ENST00000907990, ENST00000907991, ENST00000927210, ENST00000968870, ENST00000968871

RefSeq mRNA: 2 — MANE Select: NM_001666 NM_001164741, NM_001666

CCDS: CCDS14736, CCDS55540

Canonical transcript exons

ENST00000350060 — 22 exons

Exon	Start	End
ENSE00000000241	153926136	153926264
ENSE00003461781	153921097	153921159
ENSE00003476325	153913778	153913879
ENSE00003490357	153910506	153910611
ENSE00003497479	153910700	153910834
ENSE00003498448	153920626	153920808
ENSE00003538975	153910171	153910404
ENSE00003551389	153909070	153909169
ENSE00003554262	153921605	153921809
ENSE00003564782	153910012	153910085
ENSE00003595075	153913409	153913600
ENSE00003597168	153907378	153907962
ENSE00003605331	153913218	153913302
ENSE00003608590	153911129	153911189
ENSE00003635447	153921365	153921527
ENSE00003639315	153912700	153912802
ENSE00003645434	153918832	153919053
ENSE00003651638	153919155	153919283
ENSE00003654868	153909443	153909535
ENSE00003675385	153910922	153910999
ENSE00003690956	153913024	153913051
ENSE00003785888	153909741	153909924

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 99.36.

FANTOM5 (CAGE): breadth broad, TPM avg 12.1186 / max 486.9809, expressed in 801 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200927	78.0360	1822
200925	9.4561	777
200924	2.2357	476
200926	0.4268	162

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.36	gold quality
spleen	UBERON:0002106	97.94	gold quality
monocyte	CL:0000576	97.47	gold quality
mononuclear cell	CL:0000842	97.09	gold quality
leukocyte	CL:0000738	96.97	gold quality
lymph node	UBERON:0000029	96.44	gold quality
blood	UBERON:0000178	95.89	gold quality
right lung	UBERON:0002167	95.44	gold quality
upper lobe of left lung	UBERON:0008952	95.00	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.99	gold quality
vermiform appendix	UBERON:0001154	94.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.15	gold quality
cerebellar hemisphere	UBERON:0002245	94.10	gold quality
cerebellar cortex	UBERON:0002129	93.95	gold quality
metanephros cortex	UBERON:0010533	93.54	gold quality
apex of heart	UBERON:0002098	93.53	gold quality
right uterine tube	UBERON:0001302	93.41	gold quality
upper lobe of lung	UBERON:0008948	93.29	gold quality
omental fat pad	UBERON:0010414	93.07	gold quality
peritoneum	UBERON:0002358	93.03	gold quality
small intestine	UBERON:0002108	92.50	gold quality
right coronary artery	UBERON:0001625	92.47	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.23	gold quality
caecum	UBERON:0001153	92.22	gold quality
cerebellum	UBERON:0002037	92.18	gold quality
transverse colon	UBERON:0001157	91.97	gold quality
left uterine tube	UBERON:0001303	91.86	gold quality
bone marrow cell	CL:0002092	91.51	gold quality
right adrenal gland cortex	UBERON:0035827	91.47	gold quality
mucosa of transverse colon	UBERON:0004991	91.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.37
E-MTAB-4850	no	972.34

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting ARHGAP4, 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-3667-3P	99.99	67.17	1636
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-4303	98.01	68.13	2304

Literature-anchored findings (GeneRIF, showing 14)

• A novel type of contiguous gene deletion of ARHGAP4 has been identified in unrelated Japanese kindreds with nephrogenic diabetes insipidus. (PMID:11754100)
• FNBP2, ARHGAP13, ARHGAP14 and ARHGAP4 constitute the FNBP2 family characterized by FCH, RhoGAP and SH3 domains. (PMID:12736724)
• ARHGAP4 may play some role in lymphocyte differentiation but partial loss of ARHGAP4 does not result in clinical immunodeficiency (PMID:18489790)
• PRL-1 binding to p115 RhoGAP provides a coordinated mechanism underlying ERK1/2 and RhoA activation (PMID:22009749)
• X-linked nephrogenic diabetes insipidus (NDI) and intellectual disability in two dizygotic twin brothers was caused by a novel contiguous deletion of 17,905 bp of the entire AVPR2 gene and intron 7 of the ARHGAP4 gene. (PMID:22965914)
• ARHGAP4 rs2269368 was associated with risk of schizophrenia in a Han Chinese population. (PMID:24043878)
• The relation between ARHGAP4 mutation and Mental retardation(MR) clinical characteristic is needed to be illuminated with participation of more MR patients (PMID:26707211)
• ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/beta-catenin signaling pathway. (PMID:30958531)
• Comprehensive analysis on the whole Rho-GAP family reveals that ARHGAP4 suppresses EMT in epithelial cells under negative regulation by Septin9. (PMID:32378260)
• ARHGAP4-SEPT2-SEPT9 complex enables both up- and down-modulation of integrin-mediated focal adhesions, cell migration, and invasion. (PMID:34524873)
• Candidate Oncogenes, ARHGAP4, NOS3, and OR51B5, for the Development of Scirrhous-type Gastric Cancer. (PMID:36288877)
• ARHGAP4 promotes leukemogenesis in acute myeloid leukemia by inhibiting DRAM1 signaling. (PMID:37443303)
• Rho GTPase-activating protein 4 is upregulated in Kidney Renal Clear Cell Carcinoma and associated with poor prognosis and immune infiltration. (PMID:38905034)
• ARHGAP4 variants are associated with X-linked early-onset temporal lobe epilepsy. (PMID:39060771)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgap4b	ENSDARG00000015003
danio_rerio	arhgap4a	ENSDARG00000039265
mus_musculus	Arhgap4	ENSMUSG00000031389
rattus_norvegicus	Arhgap4	ENSRNOG00000058545
caenorhabditis_elegans		WBGENE00006406

Paralogs (5): SRGAP2C (ENSG00000171943), SRGAP3 (ENSG00000196220), SRGAP2B (ENSG00000196369), SRGAP1 (ENSG00000196935), SRGAP2 (ENSG00000266028)

Protein

Protein identifiers

Rho GTPase-activating protein 4 — P98171 (reviewed: P98171)

Alternative names: Rho-GAP hematopoietic protein C1, Rho-type GTPase-activating protein 4, p115

All UniProt accessions (13): P98171, A0A0B4J1X7, A0A8V8TPJ2, C9J5M2, C9JLA8, E7EQN5, E9PCM6, F8WAR0, H7C120, H7C2Z8, H7C3G3, H7C3K8, S4R314

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory effect on stress fiber organization. May down-regulate Rho-like GTPase in hematopoietic cells.

Subunit / interactions. Interacts with NCKAP1L.

Subcellular location. Cytoplasm.

Tissue specificity. Predominantly in hematopoietic cells (spleen, thymus and leukocytes); low levels in placenta, lung and various fetal tissues.

Isoforms (2)

UniProt ID	Names	Canonical?
P98171-1	1	yes
P98171-2	2

RefSeq proteins (2): NP_001158213, NP_001657* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001060	FCH_dom	Domain
IPR001452	SH3_domain	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR031160	F_BAR_dom	Domain
IPR035678	srGAP4_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051627	SLIT-ROBO_RhoGAP	Family

Pfam: PF00611, PF00620, PF14604

UniProt features (25 total): compositionally biased region 5, strand 4, domain 3, modified residue 3, region of interest 3, sequence conflict 2, chain 1, site 1, splice variant 1, sequence variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2EPD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98171-F1	76.48	0.51

Functional residue map

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

Catalytic / active sites (1): 543 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (3): 860, 901, 906

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle

MSigDB gene sets: 255 (showing top): BIOCARTA_RHO_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GCM_MSN, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, MODULE_45, GOBP_GROWTH, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, DARWICHE_SKIN_TUMOR_PROMOTER_UP, GOBP_REGULATION_OF_FIBROBLAST_MIGRATION, DARWICHE_PAPILLOMA_RISK_LOW_DN

GO Biological Process (9): cytoskeleton organization (GO:0007010), Rho protein signal transduction (GO:0007266), nervous system development (GO:0007399), negative regulation of fibroblast migration (GO:0010764), negative regulation of cell migration (GO:0030336), negative regulation of axon extension (GO:0030517), regulation of small GTPase mediated signal transduction (GO:0051056), regulation of synapse assembly (GO:0051963), signal transduction (GO:0007165)

GO Molecular Function (3): GTPase activator activity (GO:0005096), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), microtubule (GO:0005874), growth cone (GO:0030426)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
small GTPase-mediated signal transduction	2
organelle organization	1
system development	1
fibroblast migration	1
regulation of fibroblast migration	1
negative regulation of cell migration	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
negative regulation of cell growth	1
regulation of axon extension	1
negative regulation of developmental growth	1
axon extension	1
negative regulation of axonogenesis	1
regulation of intracellular signal transduction	1
synapse assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
protein binding	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
site of polarized growth	1
distal axon	1

Protein interactions and networks

STRING

1048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP4	AVPR2	P30518	866
ARHGAP4	RALGAPA1	Q6GYQ0	622
ARHGAP4	FCHSD1	Q86WN1	567
ARHGAP4	PTP4A1	Q93096	501
ARHGAP4	TRIP10	Q15642	452
ARHGAP4	ARHGEF37	A1IGU5	446
ARHGAP4	FNBP1	Q96RU3	437
ARHGAP4	UBR3	Q6ZT12	423
ARHGAP4	FNBP1L	Q5T0N5	399
ARHGAP4	PACSIN1	Q9BY11	394
ARHGAP4	TMEM187	Q14656	393
ARHGAP4	LRCH3	Q96II8	392
ARHGAP4	RENBP	P51606	386
ARHGAP4	DNMBP	Q6XZF7	384
ARHGAP4	MTSS2	Q765P7	383

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ARHGAP4	HMGN2	psi-mi:“MI:0915”(physical association)	0.400
ARHGAP4	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
FASLG	ARHGAP4	psi-mi:“MI:0915”(physical association)	0.400
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
FAM167A	IFT56	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
ZNF252P-AS1	INPP4B	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
ARHGAP4	ftsZ	psi-mi:“MI:0915”(physical association)	0.000
rdgC	ARHGAP4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): PCBP1 (Co-fractionation), ARHGAP4 (Affinity Capture-RNA), ARHGAP4 (Reconstituted Complex), ARHGAP4 (Affinity Capture-RNA), ARHGAP4 (Proximity Label-MS), HIST1H2BH (Proximity Label-MS), ARHGAP4 (FRET), ARHGAP4 (Affinity Capture-MS), CSTA (Affinity Capture-MS), RANBP9 (Affinity Capture-MS), SMARCC2 (Affinity Capture-MS), ANKFY1 (Affinity Capture-MS), CAMSAP3 (Affinity Capture-MS), MYCBP (Affinity Capture-MS), RPS29 (Affinity Capture-MS)

ESM2 similar proteins: A0JNG4, A1L3T7, B1AVH7, B5DFA1, D2H0G5, E1U8D0, E9QHE3, I1VZH0, O08629, O60826, O75052, O94964, P58660, P86182, P98171, Q13263, Q149G0, Q1LWB0, Q1RMI8, Q3ULW6, Q3V3A7, Q571B6, Q58D79, Q5JV73, Q5R8S0, Q62318, Q6P4K6, Q6PGG2, Q6ZQ29, Q6ZRF8, Q768S4, Q7TSI1, Q80TQ5, Q8BL43, Q8C7B8, Q8IWE5, Q8K1S6, Q8N163, Q8TF30, Q8VDP4

Diamond homologs: A0A0G2JTR4, A1A4S6, A2AB59, A4IF90, A4II46, A6NI28, A6QNS3, A6X8Z5, A7KAX9, A7YY57, B2RQE8, B2RTY4, B5DFQ4, D3ZZN9, E7EZG2, E7F3F0, F1LXF1, O14014, O14559, O60890, O94466, P0CAX5, P11274, P15882, P30337, P34288, P38339, P39960, P46941, P52757, P81128, P97393, P98171, Q03070, Q08DP6, Q12979, Q13017, Q17QN0, Q20498, Q2M1Z3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARHGAP4	“down-regulates activity”	RAC1	“gtpase-activating protein”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	1
Uncertain significance	128
Likely benign	26
Benign	10

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1077181	Single allele	Pathogenic
1341085	GRCh37/hg19 Xq28(chrX:153093501-153792322)x2	Pathogenic
146576	GRCh38/hg38 Xq28(chrX:153855152-154092314)x2	Pathogenic
148069	GRCh38/hg38 Xq28(chrX:153813894-154140759)x2	Pathogenic
151839	GRCh38/hg38 Xq28(chrX:153813894-154383071)x2	Pathogenic
151852	GRCh38/hg38 Xq28(chrX:153802827-154294817)x2	Pathogenic
1526875	GRCh37/hg19 Xq28(chrX:153105394-153421839)	Pathogenic
1526877	GRCh37/hg19 Xq28(chrX:153135263-153594168)	Pathogenic
155047	GRCh38/hg38 Xq28(chrX:153861449-154140759)x2	Pathogenic
253510	GRCh37/hg19 Xq28(chrX:153047627-153555804)x2	Pathogenic
3062535	GRCh37/hg19 Xq28(chrX:153180240-153421839)	Pathogenic
3066030	NC_000023.11:g.153670446_154329698dup	Pathogenic
3391867	GRCh37/hg19 Xq28(chrX:153135258-153408000)x3	Pathogenic
4077392	NC_000023.11:g.153902531_153911235del	Pathogenic
4279373	GRCh37/hg19 Xq28(chrX:153180241-153421839)x2	Pathogenic
4683033	GRCh37/hg19 Xq28(chrX:153061957-153438781)x2	Pathogenic
4796049	GRCh38/hg38 Xq28(chrX:153828334-154347735)x2	Pathogenic
523295	GRCh37/hg19 Xq28(chrX:153138672-153665655)	Pathogenic
58740	GRCh38/hg38 Xq28(chrX:153769547-154394658)x2	Pathogenic
58741	GRCh38/hg38 Xq28(chrX:153777340-154397779)x3	Pathogenic
58742	GRCh38/hg38 Xq28(chrX:153787044-154397779)x2	Pathogenic
665050	NC_000023.10:g.(?152990712)(153650075_?)del	Pathogenic
685402	GRCh37/hg19 Xq28(chrX:153154008-153624566)x2	Pathogenic
685608	GRCh37/hg19 Xq28(chrX:153105400-153438105)x2	Pathogenic
816414	GRCh37/hg19 Xq28(chrX:153029046-153567369)x3	Pathogenic
980882	GRCh37/hg19 Xq28(chrX:153113943-153624215)x2	Pathogenic
980883	GRCh37/hg19 Xq28(chrX:153135257-153594096)x3	Pathogenic
816413	GRCh37/hg19 Xq28(chrX:153023149-153345755)x2	Likely pathogenic

SpliceAI

4157 predictions. Top by Δscore:

Variant	Effect	Δscore
X:153907959:CAGC:C	acceptor_gain	1.0000
X:153909066:TCAC:T	donor_loss	1.0000
X:153909067:CA:C	donor_loss	1.0000
X:153909069:C:A	donor_loss	1.0000
X:153909165:CTGGC:C	acceptor_gain	1.0000
X:153909166:TGGC:T	acceptor_gain	1.0000
X:153909167:GGC:G	acceptor_gain	1.0000
X:153909168:GC:G	acceptor_gain	1.0000
X:153909169:CC:C	acceptor_gain	1.0000
X:153909170:C:CC	acceptor_gain	1.0000
X:153909170:CTGCA:C	acceptor_loss	1.0000
X:153909739:AC:A	donor_gain	1.0000
X:153909740:CC:C	donor_gain	1.0000
X:153909740:CCCGG:C	donor_gain	1.0000
X:153910010:ACCAT:A	donor_gain	1.0000
X:153910011:CCATC:C	donor_gain	1.0000
X:153910014:T:TA	donor_gain	1.0000
X:153910017:T:TA	donor_gain	1.0000
X:153910205:T:TA	donor_gain	1.0000
X:153910405:C:CC	acceptor_gain	1.0000
X:153910501:CTCA:C	donor_gain	1.0000
X:153910503:CA:C	donor_loss	1.0000
X:153910504:A:AC	donor_gain	1.0000
X:153910505:C:CA	donor_gain	1.0000
X:153910505:CT:C	donor_gain	1.0000
X:153910505:CTG:C	donor_gain	1.0000
X:153910505:CTGG:C	donor_gain	1.0000
X:153910505:CTGGT:C	donor_gain	1.0000
X:153910607:CAGCT:C	acceptor_gain	1.0000
X:153910608:AGCT:A	acceptor_gain	1.0000

AlphaMissense

6093 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:153910357:G:T	A657D	0.997
X:153910770:C:A	K582N	0.997
X:153910770:C:G	K582N	0.997
X:153910978:A:G	F542S	0.997
X:153911151:G:C	C527W	0.997
X:153910350:G:C	C659W	0.996
X:153910360:A:G	L656P	0.996
X:153910380:G:C	N649K	0.996
X:153910380:G:T	N649K	0.996
X:153910766:A:C	Y584D	0.996
X:153910772:T:C	K582E	0.996
X:153910977:G:C	F542L	0.996
X:153910977:G:T	F542L	0.996
X:153910979:A:G	F542L	0.996
X:153913417:A:C	Y440D	0.996
X:153913587:A:G	L383P	0.996
X:153910264:A:T	I688K	0.995
X:153910362:G:C	N655K	0.995
X:153910362:G:T	N655K	0.995
X:153910774:A:G	L581P	0.995
X:153910783:G:T	A578D	0.995
X:153910930:A:G	F558S	0.995
X:153910979:A:T	F542I	0.995
X:153911152:C:T	C527Y	0.995
X:153911153:A:G	C527R	0.995
X:153913259:A:G	L457P	0.995
X:153913298:A:G	L444P	0.995
X:153919237:C:G	R243P	0.995
X:153909855:A:G	F767S	0.994
X:153910345:C:T	G661E	0.994

dbSNP variants (sampled 300 via entrez): RS1000204258 (X:153917695 G>A,C), RS1000293128 (X:153908509 C>A), RS1000359242 (X:153914934 T>C), RS1000406289 (X:153908277 C>T), RS1000581776 (X:153921247 G>A,C,T), RS1000811302 (X:153928042 T>C), RS1000876837 (X:153914606 G>A), RS1001098011 (X:153928205 C>A), RS1001253910 (X:153918207 G>C), RS1001486978 (X:153925073 A>T), RS1001767521 (X:153925613 G>C), RS1001942827 (X:153907230 G>A), RS1002078817 (X:153906879 C>T), RS1002141701 (X:153919922 G>A), RS1002257878 (X:153919595 C>A)

Disease associations

OMIM: gene MIM:300023 | disease phenotypes: MIM:300260, MIM:300049, MIM:304120, MIM:309350, MIM:305620, MIM:300815, MIM:304800

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Limited	X-linked

Mondo (10): syndromic X-linked intellectual disability Lubs type (MONDO:0010283), heterotopia, periventricular, X-linked dominant (MONDO:0010233), otopalatodigital syndrome type 2 (MONDO:0010571), Melnick-Needles syndrome (MONDO:0010650), frontometaphyseal dysplasia (MONDO:0015942), chromosome Xq28 duplication syndrome (MONDO:0010436), diabetes insipidus, nephrogenic, X-linked (MONDO:0010581), intellectual disability (MONDO:0001071), microcytic anemia (MONDO:0001245), X-linked Emery-Dreifuss muscular dystrophy (MONDO:0010680)

Orphanet (11): Proximal Xq28 duplication syndrome (Orphanet:1762), Frontometaphyseal dysplasia (Orphanet:1826), Nodular neuronal heterotopia (Orphanet:2149), Melnick-Needles syndrome (Orphanet:2484), OBSOLETE: Otopalatodigital syndrome (Orphanet:669), Ehlers-Danlos syndrome with periventricular heterotopia (Orphanet:82004), Otopalatodigital syndrome type 2 (Orphanet:90652), Arginine vasopressin resistance (Orphanet:223), Emery-Dreifuss muscular dystrophy (Orphanet:261), X-linked Emery-Dreifuss muscular dystrophy (Orphanet:98863), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001935	Microcytic anemia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002190_1	Schizophrenia	4.000000e-08
GCST003155_27	Systemic lupus erythematosus	2.000000e-15
GCST005987_8	Albumin-globulin ratio	8.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005128	albumin:globulin ratio measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D000083143	X-Linked Emery-Dreifuss Muscular Dystrophy	C05.651.534.500.350.500; C10.668.491.175.500.350.500; C16.320.322.625.500; C16.320.577.350.500
C567580	Chromosome Xq28 Duplication Syndrome (supp.)
C538064	Frontometaphyseal dysplasia (supp.)
C537723	Lubs X-linked mental retardation syndrome (supp.)
C538089	Oto-palato-digital syndrome, type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	3
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
tamibarotene	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, decreases 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	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	decreases expression	1
Catechin	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Environmental Pollutants	affects expression	1
Flavonoids	decreases expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1

Clinical trials (associated diseases)

206 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
NCT05857085	PHASE4	COMPLETED	Novel Therapeutics and Endothelial Dysfunction in T1DM Patients
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
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
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