ARHGEF6

Summary

ARHGEF6 (Rac/Cdc42 guanine nucleotide exchange factor 6, HGNC:685) is a protein-coding gene on chromosome Xq26.3, encoding Rho guanine nucleotide exchange factor 6 (Q15052). Acts as a RAC1 guanine nucleotide exchange factor (GEF).

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific cognitive disability.

Source: NCBI Gene 9459 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Supportive, GenCC) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 272 total — 7 pathogenic, 4 likely-pathogenic
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004840

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:685
Approved symbol	ARHGEF6
Name	Rac/Cdc42 guanine nucleotide exchange factor 6
Location	Xq26.3
Locus type	gene with protein product
Status	Approved
Aliases	alphaPIX, Cool-2, KIAA0006, alpha-PIX, Cool2, αPix
Ensembl gene	ENSG00000129675
Ensembl biotype	protein_coding
OMIM	300267
Entrez	9459

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000250617, ENST00000370620, ENST00000370622, ENST00000881404, ENST00000881405, ENST00000881406, ENST00000881407, ENST00000881408, ENST00000955722

RefSeq mRNA: 2 — MANE Select: NM_004840 NM_001306177, NM_004840

CCDS: CCDS14660, CCDS78509

Canonical transcript exons

ENST00000250617 — 22 exons

Exon	Start	End
ENSE00000677021	136669482	136669536
ENSE00000677022	136672020	136672119
ENSE00000677037	136708675	136708770
ENSE00000890626	136675007	136675096
ENSE00000890628	136679535	136679660
ENSE00000890630	136681890	136681968
ENSE00000890632	136685677	136685823
ENSE00000890633	136687932	136687991
ENSE00000890634	136690610	136690748
ENSE00000890635	136706908	136707030
ENSE00000890636	136713276	136713370
ENSE00000890637	136732102	136732172
ENSE00000979461	136780718	136780932
ENSE00000979462	136779414	136779497
ENSE00001246193	136680731	136680876
ENSE00001436482	136676624	136676717
ENSE00001436514	136677936	136677956
ENSE00001617240	136682758	136682844
ENSE00003477562	136747508	136747592
ENSE00003584294	136745223	136745347
ENSE00003665844	136743585	136743786
ENSE00003846287	136665550	136668169

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 96.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4720 / max 649.4631, expressed in 1431 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200667	6.6301	535
200668	5.1393	572
200662	2.9162	1202
200661	1.6163	641
200671	0.9004	322
200660	0.6591	242
200663	0.5948	305
200670	0.4935	216
200674	0.3629	105
200664	0.3535	156

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	96.48	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.38	gold quality
medial globus pallidus	UBERON:0002477	96.01	gold quality
vastus lateralis	UBERON:0001379	95.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.42	gold quality
quadriceps femoris	UBERON:0001377	95.41	gold quality
globus pallidus	UBERON:0001875	95.26	gold quality
heart right ventricle	UBERON:0002080	95.19	gold quality
tibia	UBERON:0000979	94.74	gold quality
calcaneal tendon	UBERON:0003701	94.74	gold quality
mononuclear cell	CL:0000842	94.67	gold quality
monocyte	CL:0000576	94.65	gold quality
leukocyte	CL:0000738	94.64	gold quality
trabecular bone tissue	UBERON:0002483	94.55	gold quality
skeletal muscle tissue	UBERON:0001134	94.29	gold quality
visceral pleura	UBERON:0002401	94.25	gold quality
tendon	UBERON:0000043	94.18	gold quality
parietal pleura	UBERON:0002400	94.18	gold quality
pleura	UBERON:0000977	94.13	gold quality
epithelium of mammary gland	UBERON:0003244	93.80	gold quality
synovial joint	UBERON:0002217	93.79	gold quality
triceps brachii	UBERON:0001509	93.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.75	gold quality
gluteal muscle	UBERON:0002000	93.74	gold quality
deltoid	UBERON:0001476	93.66	gold quality
mammary duct	UBERON:0001765	93.61	gold quality
superficial temporal artery	UBERON:0001614	93.29	gold quality
thoracic mammary gland	UBERON:0005200	93.26	gold quality
mammary gland	UBERON:0001911	93.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.17	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	14.02
E-CURD-112	yes	12.84
E-MTAB-9067	yes	12.83
E-HCAD-10	yes	6.36
E-ANND-3	yes	5.52
E-MTAB-6678	no	4.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

127 targeting ARHGEF6, 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-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 19)

• The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding (PMID:11937491)
• Expression of Cbl-b effectively blocks the ability of Cool-2 to stimulate PAK, providing an additional mechanism, aside from catalyzing receptor ubiquitination, by which Cbl-b acts as a negative regulator for signaling activities requiring PAK activation. (PMID:12935897)
• Data suggest that Rac-dependent activation of the NFkappaB pathway may be a critical element promoting thrombin-induced tissue factor expression and activity, and thus a prothrombotic state in pulmonary hypertension. (PMID:15242552)
• Whereas alphaPIX guanine nucleotide exchange factor activity contributes to enhanced formation of cellular protrusions, the GEF-independent association with calpain 4 leads to induction of a yet unknown signaling cascade resulting in cell spreading. (PMID:15611136)
• Semi-quantitative RT-PCR experiments with 6 of those genes confirmed higher expression of DNCH2, ARHGEF6, NPM1 and SRI and lower expression of NRGN and TM4SF2 in GBM tumors. (PMID:16320026)
• PAK4 and alphaPIX can induce highly localized changes in actin dynamics and thereby regulate size and number of podosomes in primary human macrophages. (PMID:16897755)
• phosphorylation of CagA induces the dephosphorylation of alpha-Pix, which may modulate cytoskeletal changes of gastric epithelial cells through PAK (PMID:17405911)
• The interaction of alphaPix with CagA activates PAK1, ERK and NF-kappaB, which induces IL-8 expression in H. pylori-infected gastric epithelial cells. (PMID:19672789)
• results suggest that low doses of chlorambucil and very low doses of chronic oxidative stress together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl(cos) cells. (PMID:19918261)
• These findings suggest that alpha Pix plays an important role in mutant huntingtin aggregation. (PMID:19969308)
• c-Cbl negatively regulates alphaPix-mediated cell migration and invasion; the lack of c-Cbl in C6 and A172 glioma cells is responsible for their malignant behavior (PMID:25450678)
• The novel recycling regulator alpha-PIX and the degradation factor c-Cbl closely cooperate in the regulation of EGFR trafficking. (PMID:26177020)
• show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex (PMID:26507661)
• we discuss recent findings in key physiological systems that exemplify current understanding of the function of this important regulatory complex. Further, we draw attention to gaps in crucial information that remain to be filled to allow a better understanding of the many roles of the GIT-PIX complex in health and disease (PMID:27182061)
• In this first X chromosome-wide association study of adult patients with IBD, we identified an IBD susceptibility locus with genome-wide significance at rs2427870 on chrXq26.3, located 66 kbp upstream of CD40LG and 83.4 kbp upstream of ARHGEF6 [OR, 1.22; combined p = 3.79 x 10-15]. (PMID:28333213)
• Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs. (PMID:36414417)
• Comprehensive analysis identifies ARHGEF6 as a potential prognostic and immunological biomarker in lung adenocarcinoma. (PMID:36586227)
• Clinical implication and potential function of ARHGEF6 in acute myeloid leukemia: An in vitro study. (PMID:37027440)
• The pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma. (PMID:37058762)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef6	ENSDARG00000006683
mus_musculus	Arhgef6	ENSMUSG00000031133
rattus_norvegicus	Arhgef6	ENSRNOG00000000869

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 6 — Q15052 (reviewed: Q15052)

Alternative names: Alpha-Pix, COOL-2, PAK-interacting exchange factor alpha, Rac/Cdc42 guanine nucleotide exchange factor 6

All UniProt accessions (1): Q15052

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a RAC1 guanine nucleotide exchange factor (GEF).

Subunit / interactions. Interacts with PAK kinases through the SH3 domain. Interacts with GIT1. Component of cytoplasmic complexes, which also contain PXN, GIT1 and PAK1. Interacts with PARVB. Interacts with BIN2. Identified in a complex with BIN2 and GIT2. Interacts with PARVG; the guanine nucleotide exchange factor activity of ARHGEF6 is essential for PARVG-induced enhancement of cell spreading.

Subcellular location. Cell projection. Lamellipodium.

Tissue specificity. Ubiquitous.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15052-1	1	yes
Q15052-2	2

RefSeq proteins (2): NP_001293106, NP_004831* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001452	SH3_domain	Domain
IPR001715	CH_dom	Domain
IPR001849	PH_domain	Domain
IPR003096	SM22_calponin	Family
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR032409	GEF6/7_CC	Domain
IPR035788	AlphaPIX_SH3	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR046376	PH_Cool_Pix	Domain

Pfam: PF00169, PF00307, PF00621, PF07653, PF16523, PF16614, PF16615

UniProt features (34 total): modified residue 8, helix 7, strand 6, domain 4, region of interest 2, compositionally biased region 2, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1UJY	SOLUTION NMR
1WYR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15052-F1	71.85	0.28

Functional residue map

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

Post-translational modifications (8): 133, 144, 150, 225, 488, 640, 684, 126

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-446388	Regulation of cytoskeletal remodeling and cell spreading by IPP complex components
R-HSA-8964616	G beta:gamma signalling through CDC42
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013420	RHOU GTPase cycle
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-397795	G-protein beta:gamma signalling
R-HSA-446353	Cell-extracellular matrix interactions
R-HSA-446728	Cell junction organization
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 261 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, PEREZ_TP63_TARGETS, GCANCTGNY_MYOD_Q6, MODULE_45, AAGCCAT_MIR135A_MIR135B, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, MODULE_16, CAGCTG_AP4_Q5, GTGCCTT_MIR506, MODULE_118, CEBP_Q2, GOBP_JNK_CASCADE, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, TGACATY_UNKNOWN, IRF_Q6

GO Biological Process (3): apoptotic process (GO:0006915), JNK cascade (GO:0007254), lamellipodium assembly (GO:0030032)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), cell-cell junction (GO:0005911), lamellipodium (GO:0030027), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
RHO GTPase cycle	3
Signal Transduction	3
GPCR downstream signalling	2
Cell death signalling via NRAGE, NRIF and NADE	1
Cell-extracellular matrix interactions	1
G-protein beta:gamma signalling	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1
Cell junction organization	1
Cell-Cell communication	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
GTPase regulator activity	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
MAPK cascade	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
anchoring junction	1
cell leading edge	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF6	GIT1	Q9Y2X7	998
ARHGEF6	PARVB	Q9HBI1	993
ARHGEF6	GIT2	Q14161	991
ARHGEF6	PXN	P49023	945
ARHGEF6	CDC42	P21181	937
ARHGEF6	PAK3	O75914	887
ARHGEF6	NCK1	P16333	882
ARHGEF6	ILK	P57043	863
ARHGEF6	OPHN1	O60890	843
ARHGEF6	RABIF	P47224	824
ARHGEF6	GOLPH3	Q9H4A6	808
ARHGEF6	GRK4	P32298	807
ARHGEF6	GRK6	P43250	774
ARHGEF6	RASA1	P20936	763
ARHGEF6	GRK5	P34947	736

IntAct

137 interactions, top by confidence:

A	B	Type	Score
ARHGEF7	PAK1	psi-mi:“MI:0914”(association)	0.950
PAK1	NCK2	psi-mi:“MI:0914”(association)	0.940
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
PAK2	NCK2	psi-mi:“MI:0914”(association)	0.840
PAK2	ARHGEF6	psi-mi:“MI:0915”(physical association)	0.830
SCRIB	ADRA1D	psi-mi:“MI:0914”(association)	0.820
ARHGEF6	PAK1	psi-mi:“MI:0914”(association)	0.800
ARHGEF6	PAK1	psi-mi:“MI:0915”(physical association)	0.800
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
MED4	MED14	psi-mi:“MI:0914”(association)	0.740
SCRIB	PPP1CC	psi-mi:“MI:0914”(association)	0.730
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
ARHGEF7	NCK2	psi-mi:“MI:0914”(association)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
PFDN1	PFDN6	psi-mi:“MI:0914”(association)	0.640
LPXN	PCNT	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
GIT2	ARHGEF6	psi-mi:“MI:0915”(physical association)	0.630
ARHGEF6	GIT2	psi-mi:“MI:0915”(physical association)	0.630
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610

BioGRID (149): ARHGEF6 (Affinity Capture-MS), ARHGEF6 (Affinity Capture-MS), ARHGEF6 (Affinity Capture-MS), ARHGEF6 (Affinity Capture-Western), ARHGEF6 (Affinity Capture-MS), ARHGEF6 (Co-localization), CBL (Affinity Capture-Western), ARHGEF6 (Affinity Capture-Western), ARHGEF6 (Affinity Capture-MS), ARHGEF6 (Affinity Capture-MS), GIT1 (Affinity Capture-MS), FBXO28 (Affinity Capture-MS), ARHGEF6 (Affinity Capture-MS), PAK1 (Affinity Capture-MS), ARHGEF6 (Affinity Capture-MS)

ESM2 similar proteins: A0JM23, A0M8T3, A1X154, A6H7D1, A7MBF6, A8Y5U1, B1WC10, E9Q9R9, F1M649, F1MHT9, O00750, O88480, O95876, P0CI65, P50851, Q008S8, Q00PJ3, Q07E17, Q07E30, Q07E43, Q09YN0, Q108U1, Q15052, Q2IBF5, Q2IBG0, Q2QLA4, Q2QLB5, Q32NR4, Q32NR9, Q3UP24, Q3V129, Q4V7F0, Q5XXR3, Q5ZLR6, Q692V3, Q6AZT7, Q6P2S7, Q6P3V7, Q6PIY5, Q6ZS30

Diamond homologs: A1A5G4, A5PKA5, A8JQ65, A8MUH7, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, B7WN72, D3YXJ0, D3YZU1, E9PUQ8, O14745, O43639, O55033, O55043, P15498, P16333, P27870, P54100, P70441, Q08DN7, Q14155, Q15052, Q15599, Q16760, Q28619, Q3SZK8, Q3T0X8, Q3UHD6, Q4ACU6, Q4R6G4, Q52KW0, Q570Y9, Q5F488, Q5RCF7, Q5T2W1

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
PRKACA	“down-regulates activity”	ARHGEF6	phosphorylation
PKA	“down-regulates activity”	ARHGEF6	phosphorylation
PKC	“down-regulates activity”	ARHGEF6	phosphorylation
GIT1	“up-regulates activity”	ARHGEF6	binding
ARHGEF6	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
ASAP3	“up-regulates activity”	ARHGEF6	binding
ARHGEF6	up-regulates	Actin_cytoskeleton_reorganization
ARHGEF6	up-regulates	Cell_migration
PRKCQ	“up-regulates activity”	ARHGEF6	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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
Ephrin signaling	5	50.1×	4e-06
RHOV GTPase cycle	8	40.1×	3e-09
RHOU GTPase cycle	8	39.1×	3e-09
RHOQ GTPase cycle	9	28.6×	3e-09
RHOJ GTPase cycle	7	24.6×	1e-06
VEGFA-VEGFR2 Pathway	5	12.2×	1e-03
CDC42 GTPase cycle	9	11.4×	5e-06
RAC2 GTPase cycle	5	11.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	22.1×	2e-03
transforming growth factor beta receptor signaling pathway	5	10.2×	9e-03
cell migration	8	6.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	78
Likely benign	17
Benign	5

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1341130	GRCh37/hg19 Xq26.3(chrX:135767906-136348117)x3	Pathogenic
224866	GRCh37/hg19 Xq26.3(chrX:135602028-136259908)x2	Pathogenic
2427163	NC_000023.10:g.(?135730408)(136113833_?)dup	Pathogenic
243065	Single allele	Pathogenic
4075950	GRCh37/hg19 Xq26.3(chrX:135570201-136357524)x2	Pathogenic
58686	GRCh38/hg38 Xq26.3-27.1(chrX:136522136-140417943)x2	Pathogenic
58687	GRCh38/hg38 Xq26.3(chrX:136613664-137581772)x3	Pathogenic
374409	Single allele	Likely pathogenic
374410	Single allele	Likely pathogenic
374411	Single allele	Likely pathogenic
374412	Single allele	Likely pathogenic

SpliceAI

3401 predictions. Top by Δscore:

Variant	Effect	Δscore
X:136669478:TTAC:T	donor_loss	1.0000
X:136669479:TAC:T	donor_loss	1.0000
X:136669480:ACCTG:A	donor_loss	1.0000
X:136669481:CCT:C	donor_loss	1.0000
X:136669481:CCTG:C	donor_gain	1.0000
X:136669532:GGCTC:G	acceptor_gain	1.0000
X:136669534:CTC:C	acceptor_gain	1.0000
X:136669535:TC:T	acceptor_gain	1.0000
X:136669536:CC:C	acceptor_gain	1.0000
X:136669537:C:A	acceptor_loss	1.0000
X:136669537:C:CC	acceptor_gain	1.0000
X:136669538:T:C	acceptor_loss	1.0000
X:136672015:CTCA:C	donor_gain	1.0000
X:136672016:TCA:T	donor_loss	1.0000
X:136672017:CA:C	donor_loss	1.0000
X:136672018:A:AC	donor_gain	1.0000
X:136672019:C:CT	donor_gain	1.0000
X:136672019:CT:C	donor_gain	1.0000
X:136672019:CTT:C	donor_gain	1.0000
X:136672019:CTTT:C	donor_gain	1.0000
X:136672019:CTTTT:C	donor_gain	1.0000
X:136672116:GTAC:G	acceptor_gain	1.0000
X:136672117:TAC:T	acceptor_gain	1.0000
X:136672120:C:G	acceptor_loss	1.0000
X:136672121:T:A	acceptor_loss	1.0000
X:136672128:A:T	acceptor_gain	1.0000
X:136672133:T:C	acceptor_gain	1.0000
X:136675005:A:AC	donor_gain	1.0000
X:136675006:C:CC	donor_gain	1.0000
X:136676622:A:AC	donor_gain	1.0000

AlphaMissense

5085 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:136668114:A:G	L749P	1.000
X:136669489:A:G	L728P	1.000
X:136675049:C:G	A665P	1.000
X:136675063:A:G	L660P	1.000
X:136675063:A:T	L660H	1.000
X:136690677:A:G	L373P	1.000
X:136743605:A:T	V214D	1.000
X:136743617:G:T	P210H	1.000
X:136743618:G:A	P210S	1.000
X:136743618:G:T	P210T	1.000
X:136743620:A:G	F209S	1.000
X:136743622:C:A	W208C	1.000
X:136743622:C:G	W208C	1.000
X:136743624:A:G	W208R	1.000
X:136743624:A:T	W208R	1.000
X:136743626:C:T	G207D	1.000
X:136743647:C:T	G200D	1.000
X:136743648:C:G	G200R	1.000
X:136743654:A:G	W198R	1.000
X:136743654:A:T	W198R	1.000
X:136743655:C:A	W197C	1.000
X:136743655:C:G	W197C	1.000
X:136743657:A:G	W197R	1.000
X:136743657:A:T	W197R	1.000
X:136743680:A:T	V189D	1.000
X:136743710:A:G	L179P	1.000
X:136743733:A:C	F171L	1.000
X:136743733:A:T	F171L	1.000
X:136743735:A:G	F171L	1.000
X:136743739:G:C	F169L	1.000

dbSNP variants (sampled 300 via entrez): RS1000002900 (X:136713482 C>G), RS1000072443 (X:136736163 G>C), RS1000085160 (X:136691926 T>A), RS1000163738 (X:136697836 A>C,G), RS1000166526 (X:136779575 C>G), RS1000208792 (X:136764005 G>A), RS1000311937 (X:136705215 G>A), RS1000363156 (X:136698560 G>T), RS1000363654 (X:136754758 G>A), RS1000382286 (X:136731653 G>T), RS1000488173 (X:136718160 A>G), RS1000533025 (X:136777420 A>AT), RS1000534708 (X:136667502 G>A), RS1000538900 (X:136716082 A>G), RS1000666561 (X:136719445 A>G)

Disease associations

OMIM: gene MIM:300267 | disease phenotypes: MIM:300436, MIM:308350, MIM:300942, MIM:603896

GenCC curated gene-disease

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Supportive	X-linked
congenital anomaly of kidney and urinary tract	Limited	X-linked
complex neurodevelopmental disorder	Limited	Autosomal dominant
X-linked intellectual disability	Limited	X-linked
intellectual disability, X-linked 46	Limited	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	Disputed	XL

Mondo (9): intellectual disability, X-linked 46 (MONDO:0010326), intellectual disability (MONDO:0001071), genetic developmental and epileptic encephalopathy (MONDO:0100062), X-linked acrogigantism due to Xq26 microduplication (MONDO:0010491), leukoencephalopathy with vanishing white matter (MONDO:0800448), congenital anomaly of kidney and urinary tract (MONDO:0019719), complex neurodevelopmental disorder (MONDO:0100038), X-linked intellectual disability (MONDO:0100284), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (6): X-linked non-syndromic intellectual disability (Orphanet:777), X-linked acrogigantism (Orphanet:300373), OBSOLETE: X-linked acrogigantism due to Xq26 microduplication (Orphanet:448372), CACH syndrome (Orphanet:135), Ovarioleukodystrophy (Orphanet:99853), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004988_267	Breast cancer	1.000000e-11
GCST012466_7	Autism spectrum disorder	4.000000e-06

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C566906	Cakut (supp.)
C564513	Mental Retardation, X-Linked 46 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725019 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Cisplatin	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	affects expression	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	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
(+)-JQ1 compound	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
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Cadmium	decreases expression	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Demecolcine	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697790	Binding	Inhibition of ARHGEF6 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

216 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
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
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
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
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)
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
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
NCT06500260	Not specified	RECRUITING	CNKSR2 Natural History Study
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