ARHGAP6

Summary

ARHGAP6 (Rho GTPase activating protein 6, HGNC:676) is a protein-coding gene on chromosome Xp22.2, encoding Rho GTPase-activating protein 6 (O43182). GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.

This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 395 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 276 total — 5 pathogenic, 5 likely-pathogenic
• MANE Select transcript: NM_013427

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:676
Approved symbol	ARHGAP6
Name	Rho GTPase activating protein 6
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	rhoGAPX-1
Ensembl gene	ENSG00000047648
Ensembl biotype	protein_coding
OMIM	300118
Entrez	395

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000303025, ENST00000337414, ENST00000380717, ENST00000380718, ENST00000380736, ENST00000489330, ENST00000491514, ENST00000495242, ENST00000657361

RefSeq mRNA: 4 — MANE Select: NM_013427 NM_001287242, NM_006125, NM_013423, NM_013427

CCDS: CCDS14140, CCDS14141, CCDS14142

Canonical transcript exons

ENST00000337414 — 13 exons

Exon	Start	End
ENSE00003459810	11196925	11196996
ENSE00003464919	11137544	11139530
ENSE00003470444	11254548	11254707
ENSE00003495842	11169505	11169684
ENSE00003509207	11188728	11188984
ENSE00003532966	11179302	11179452
ENSE00003584918	11186236	11186431
ENSE00003585755	11142233	11142313
ENSE00003592237	11156529	11156626
ENSE00003593658	11178100	11178248
ENSE00003601968	11182063	11182118
ENSE00003689660	11143980	11144248
ENSE00003847253	11664241	11665920

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 98.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1204 / max 231.3015, expressed in 954 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198422	5.6917	823
198433	0.4585	154
198431	0.2110	90
198413	0.2047	73
198432	0.1879	57
198411	0.1345	47
198417	0.1123	71
198423	0.0750	19
198412	0.0277	10
198415	0.0172	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	98.07	gold quality
cauda epididymis	UBERON:0004360	96.10	gold quality
choroid plexus epithelium	UBERON:0003911	91.30	gold quality
parietal pleura	UBERON:0002400	91.14	gold quality
lower lobe of lung	UBERON:0008949	90.68	gold quality
pleura	UBERON:0000977	90.16	gold quality
germinal epithelium of ovary	UBERON:0001304	89.80	gold quality
visceral pleura	UBERON:0002401	89.68	gold quality
prostate gland	UBERON:0002367	89.40	gold quality
urethra	UBERON:0000057	88.97	gold quality
corpus epididymis	UBERON:0004359	88.45	gold quality
thyroid gland	UBERON:0002046	87.94	gold quality
left lobe of thyroid gland	UBERON:0001120	87.75	gold quality
mucosa of urinary bladder	UBERON:0001259	87.23	gold quality
right lung	UBERON:0002167	87.10	gold quality
right lobe of thyroid gland	UBERON:0001119	86.75	gold quality
urinary bladder	UBERON:0001255	85.58	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.51	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.01	gold quality
left ovary	UBERON:0002119	84.85	gold quality
saphenous vein	UBERON:0007318	84.83	gold quality
blood vessel layer	UBERON:0004797	84.75	gold quality
body of uterus	UBERON:0009853	84.69	gold quality
layer of synovial tissue	UBERON:0007616	84.64	gold quality
myometrium	UBERON:0001296	84.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.91	gold quality
gastrocnemius	UBERON:0001388	83.80	gold quality
left uterine tube	UBERON:0001303	83.78	gold quality
muscle of leg	UBERON:0001383	83.59	gold quality
calcaneal tendon	UBERON:0003701	83.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	57.74
E-CURD-112	yes	37.38
E-CURD-122	yes	19.55
E-ANND-3	yes	13.63
E-MTAB-9067	yes	11.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting ARHGAP6, 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-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-369-3P	99.85	70.52	2264

Literature-anchored findings (GeneRIF, showing 8)

• Human ARHGAP6 protein possessing GTPase stimulating activity for RhoA on the catalytic properties of PLC-delta1, was studied. (PMID:18434237)
• the RhoGAP6 isoform 1 variant might serve as a biomarker for the development and progression of colorectal cancer (PMID:19960375)
• Failed ARHGAP6 expression did not appreciably alter the severity of enamel defects when AMELX was absent. (PMID:23251683)
• ARHGAP6 was found to have low expression in tumor tissues from patients with lung cancer, accompanied by high expression of MMP9 and VEGF. In A549 and H1299 cells, upregulation of ARHGAP6 inhibited tumor growth and metastasis and reduced the levels of MMP9, VEGF and pSTAT3, while the levels STAT3 were unchanged. (PMID:30816546)
• MiR-96-5p is an oncogene in lung adenocarcinoma and facilitates tumor progression through ARHGAP6 downregulation. (PMID:34338998)
• ARHGAP6 inhibits bladder cancer cell viability, migration, and invasion via beta-catenin signaling and enhances mitomycin C sensitivity. (PMID:36715867)
• RhoGAP6 interacts with COPI to regulate protein transport. (PMID:37409526)
• ARHGAP6 Suppresses Breast Cancer Tumor Growth by Promoting Ferroptosis via RhoA-ROCK1-p38 MAPK Signaling. (PMID:38287795)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000111170
mus_musculus	Arhgap6	ENSMUSG00000031355
rattus_norvegicus	Arhgap6	ENSRNOG00000003956
drosophila_melanogaster	RhoGAP102A	FBGN0259216
caenorhabditis_elegans	rga-6	WBGENE00015303

Paralogs (1): ARHGAP36 (ENSG00000147256)

Protein

Protein identifiers

Rho GTPase-activating protein 6 — O43182 (reviewed: O43182)

Alternative names: Rho-type GTPase-activating protein 6, Rho-type GTPase-activating protein RhoGAPX-1

All UniProt accessions (3): B4DN07, O43182, H7BYE6

UniProt curated annotations — full annotation on UniProt →

Function. GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Could regulate the interactions of signaling molecules with the actin cytoskeleton. Promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in kidney, heart and skeletal muscle followed by retina, lymphoblast, placenta, lung, brain, pancreas and liver.

Miscellaneous. ARHGAP6 gene undergoes X inactivation.

Isoforms (5)

UniProt ID	Names	Canonical?
O43182-1	3	yes
O43182-2	1
O43182-3	2
O43182-4	4
O43182-5	5

RefSeq proteins (4): NP_001274171, NP_006116, NP_038267, NP_038286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR037863	RHOGAP6/36	Family
IPR041852	ARHGAP6_RhoGAP	Domain

Pfam: PF00620

UniProt features (41 total): modified residue 15, compositionally biased region 8, region of interest 6, splice variant 6, chain 1, domain 1, site 1, sequence variant 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43182-F1	56.60	0.21

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): 433 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (15): 37, 264, 363, 667, 673, 680, 711, 754, 772, 777, 786, 820, 928, 931, 939

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle

MSigDB gene sets: 308 (showing top): BIOCARTA_RHO_PATHWAY, E2F_Q4, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, E2F4DP1_01, ZHAN_MULTIPLE_MYELOMA_MF_UP, SP3_Q3, GOBP_FOCAL_ADHESION_ASSEMBLY, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TATTATA_MIR374, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, TGACCTY_ERR1_Q2, GOBP_NEGATIVE_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, CTATGCA_MIR153

GO Biological Process (10): actin filament organization (GO:0007015), Rho protein signal transduction (GO:0007266), actin filament polymerization (GO:0030041), focal adhesion assembly (GO:0048041), regulation of small GTPase mediated signal transduction (GO:0051056), negative regulation of stress fiber assembly (GO:0051497), negative regulation of focal adhesion assembly (GO:0051895), positive regulation of phospholipase C/protein kinase C signal transduction (GO:0141214), positive regulation of intracellular signal transduction (GO:1902533), signal transduction (GO:0007165)

GO Molecular Function (4): GTPase activator activity (GO:0005096), phospholipase activator activity (GO:0016004), SH3 domain binding (GO:0017124), phospholipase binding (GO:0043274)

GO Cellular Component (6): cytoplasm (GO:0005737), cytosol (GO:0005829), actin filament (GO:0005884), actin cytoskeleton (GO:0015629), mitotic spindle (GO:0072686), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
small GTPase-mediated signal transduction	2
regulation of intracellular signal transduction	2
cellular anatomical structure	2
actin cytoskeleton organization	1
supramolecular fiber organization	1
actin polymerization or depolymerization	1
protein polymerization	1
cell-substrate junction assembly	1
cell-matrix adhesion	1
negative regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
negative regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of focal adhesion assembly	1
negative regulation of cell-substrate junction organization	1
negative regulation of cell junction assembly	1
phospholipase C/protein kinase C signal transduction	1
positive regulation of intracellular signal transduction	1
positive regulation of signal transduction	1
intracellular signal transduction	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
glycerophospholipase activity	1
lipase activator activity	1
protein domain specific binding	1
enzyme binding	1
intracellular anatomical structure	1
cytoplasm	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
cytoskeleton	1
spindle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1040 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP6	HCCS	P53701	925
ARHGAP6	RHOA	P06749	646
ARHGAP6	CLDN18	P56856	595
ARHGAP6	AMELX	Q99217	583
ARHGAP6	PGK1	P00558	518
ARHGAP6	CYCS	P00001	514
ARHGAP6	CDC42	P21181	501
ARHGAP6	AMBN	Q9NP70	479
ARHGAP6	MSL3	Q8N5Y2	469
ARHGAP6	SRY	Q05066	460
ARHGAP6	AMELY	Q99218	454
ARHGAP6	PTPRE	P23469	444
ARHGAP6	ODAM	A1E959	440
ARHGAP6	UNC50	Q53HI1	434
ARHGAP6	ENAM	Q9NRM1	431

IntAct

127 interactions, top by confidence:

A	B	Type	Score
ARHGAP6	SNX27	psi-mi:“MI:0407”(direct interaction)	0.610
MAST2	ARHGAP6	psi-mi:“MI:0407”(direct interaction)	0.610
MAST2	ARHGAP6	psi-mi:“MI:0915”(physical association)	0.610
ARHGAP6	MAST2	psi-mi:“MI:0407”(direct interaction)	0.610
MAP1LC3A	ARHGAP6	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
PDZK1	ARHGAP6	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI2	ARHGAP6	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	ARHGAP6	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (10): ARHGAP6 (Affinity Capture-RNA), ARHGAP6 (Affinity Capture-MS), ARHGAP6 (Affinity Capture-MS), ARHGAP6 (Affinity Capture-MS), ARHGAP6 (Affinity Capture-MS), ARHGAP6 (Protein-peptide), ARHGAP6 (Cross-Linking-MS (XL-MS)), ARHGAP6 (Affinity Capture-MS), HSP90AB1 (Cross-Linking-MS (XL-MS)), ARHGAP6 (Two-hybrid)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: A0A0G2JTR4, A1A4S6, A2RUV4, A4II46, A6NI28, A6QNS3, A6X8Z5, A8WRJ2, B2RQE8, B5DFQ4, D3ZZN9, E7EZG2, E7F3F0, F1LQX4, F1LXF1, O14014, O14559, O43182, O43295, O54834, O60890, O94466, P0CAX5, P11274, P15882, P30337, P34288, P38339, P39960, P46941, P52757, P81128, P83509, P97393, Q03070, Q08DP6, Q12979, Q13017, Q17QN0, Q17R89

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARHGAP6	“down-regulates activity”	RHOA	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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
Ras activation upon Ca2+ influx through NMDA receptor	5	52.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	2e-06
Long-term potentiation	5	44.1×	3e-06
Assembly and cell surface presentation of NMDA receptors	8	37.6×	3e-09
Neurexins and neuroligins	9	32.8×	1e-09
Protein-protein interactions at synapses	5	24.6×	5e-05
RHOQ GTPase cycle	5	16.8×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	64.6×	4e-12
protein localization to synapse	6	56.7×	1e-07
receptor clustering	7	53.9×	1e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	6	36.7×	1e-06
cell-cell adhesion	10	12.5×	7e-07
protein-containing complex assembly	7	9.8×	3e-04
regulation of small GTPase mediated signal transduction	5	8.9×	6e-03
chemical synaptic transmission	7	6.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	113
Likely benign	19
Benign	11

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
11137	NM_001142.2(AMELX):c.113del (p.Pro38fs)	Pathogenic
11143	NM_001142.2(AMELX):c.499del (p.Leu167fs)	Pathogenic
11145	NM_001142.2(AMELX):c.2T>C (p.Met1Thr)	Pathogenic
2424250	NC_000023.10:g.(?8501036)(11318732_?)del	Pathogenic
3256889	NM_001142.2(AMELX):c.167C>T (p.Pro56Leu)	Pathogenic
11139	NM_001142.2(AMELX):c.431del (p.Pro144fs)	Likely pathogenic
1323884	NM_001142.2(AMELX):c.289C>T (p.Gln97Ter)	Likely pathogenic
2445234	NM_001142.2(AMELX):c.47C>A (p.Ala16Asp)	Likely pathogenic
3598004	NM_001142.2(AMELX):c.3G>A (p.Met1Ile)	Likely pathogenic
487573	NC_000023.10:g.11633731_11797224del163494	Likely pathogenic

SpliceAI

6474 predictions. Top by Δscore:

Variant	Effect	Δscore
X:11118497:CTAG:C	acceptor_loss	1.0000
X:11118498:TAGGT:T	acceptor_loss	1.0000
X:11118499:A:AG	acceptor_gain	1.0000
X:11118499:AGGT:A	acceptor_gain	1.0000
X:11118500:G:GA	acceptor_gain	1.0000
X:11118500:GGT:G	acceptor_gain	1.0000
X:11118500:GGTG:G	acceptor_gain	1.0000
X:11118616:GCTGC:G	donor_gain	1.0000
X:11118617:CTGC:C	donor_gain	1.0000
X:11118618:TGC:T	donor_gain	1.0000
X:11118619:GC:G	donor_gain	1.0000
X:11118619:GCG:G	donor_gain	1.0000
X:11118620:CGTA:C	donor_loss	1.0000
X:11118621:G:GG	donor_gain	1.0000
X:11118621:G:T	donor_loss	1.0000
X:11118625:G:GG	donor_gain	1.0000
X:11120906:GAGA:G	acceptor_gain	1.0000
X:11142228:TTCA:T	donor_loss	1.0000
X:11142229:T:TA	donor_gain	1.0000
X:11142229:TCAC:T	donor_loss	1.0000
X:11142230:CACCT:C	donor_loss	1.0000
X:11142309:CAGAT:C	acceptor_gain	1.0000
X:11142311:GAT:G	acceptor_gain	1.0000
X:11142311:GATC:G	acceptor_loss	1.0000
X:11142312:AT:A	acceptor_gain	1.0000
X:11142313:TCT:T	acceptor_loss	1.0000
X:11142314:C:CC	acceptor_gain	1.0000
X:11142314:CTAG:C	acceptor_loss	1.0000
X:11156527:A:AC	donor_gain	1.0000
X:11156528:C:CC	donor_gain	1.0000

AlphaMissense

6307 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:11156553:A:G	L628P	1.000
X:11156589:A:G	L616P	1.000
X:11169626:A:G	L563P	1.000
X:11169629:A:G	L562P	1.000
X:11169638:C:T	G559E	1.000
X:11169639:C:G	G559R	1.000
X:11169639:C:T	G559R	1.000
X:11169644:A:C	I557R	1.000
X:11169644:A:T	I557K	1.000
X:11169650:G:T	A555D	1.000
X:11169653:A:G	L554S	1.000
X:11169655:G:C	N553K	1.000
X:11169655:G:T	N553K	1.000
X:11169667:C:A	M549I	1.000
X:11169667:C:G	M549I	1.000
X:11169667:C:T	M549I	1.000
X:11169668:A:C	M549R	1.000
X:11169668:A:G	M549T	1.000
X:11169673:A:C	N547K	1.000
X:11169673:A:T	N547K	1.000
X:11169677:C:T	G546E	1.000
X:11178173:A:G	L519P	1.000
X:11179360:C:A	R474S	1.000
X:11179360:C:G	R474S	1.000
X:11179361:C:A	R474M	1.000
X:11179361:C:G	R474T	1.000
X:11179372:T:A	K470N	1.000
X:11179372:T:G	K470N	1.000
X:11179373:T:A	K470I	1.000
X:11179376:A:G	L469P	1.000

dbSNP variants (sampled 300 via entrez): RS1000015809 (X:11376197 C>A), RS1000023079 (X:11306044 T>A,C), RS1000033435 (X:11558013 T>C), RS1000046139 (X:11545401 T>G), RS1000060741 (X:11605371 G>A), RS1000067120 (X:11317663 C>A), RS1000071266 (X:11375836 G>A), RS1000074058 (X:11614483 A>T), RS1000080959 (X:11442529 C>T), RS1000082471 (X:11498968 C>G), RS1000094352 (X:11384382 C>T), RS1000094623 (X:11321513 A>G), RS1000096194 (X:11349170 T>C), RS1000104745 (X:11557331 C>T), RS1000108764 (X:11167191 A>G)

Disease associations

OMIM: gene MIM:300118 | disease phenotypes: MIM:301200, MIM:301201

GenCC curated gene-disease

Mondo (4): amelogenesis imperfecta type 1E (MONDO:0010521), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2 (MONDO:0010522)

Orphanet (2): Amelogenesis imperfecta (Orphanet:88661), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006083_4	Prostate cancer (advanced)	1.000000e-08
GCST006085_105	Prostate cancer	2.000000e-13
GCST90002397_153	Mean spheric corpuscular volume	2.000000e-11

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
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	decreases methylation, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	decreases expression	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	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, increases expression	1
Dexamethasone	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Fluorescein-5-isothiocyanate	affects binding	1
Sodium Selenite	decreases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays