ARHGAP21

Summary

ARHGAP21 (Rho GTPase activating protein 21, HGNC:23725) is a protein-coding gene on chromosome 10p12.1, encoding Rho GTPase-activating protein 21 (Q5T5U3). Functions as a GTPase-activating protein (GAP) for RHOA and CDC42.

ARHGAP21 functions preferentially as a GTPase-activating protein (GAP) for CDC42 (MIM 116952) and regulates the ARP2/3 complex (MIM 604221) and F-actin dynamics at the Golgi through control of CDC42 activity (Dubois et al., 2005 [PubMed 15793564]).

Source: NCBI Gene 57584 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 521 total — 2 pathogenic, 4 likely-pathogenic
• MANE Select transcript: NM_020824

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23725
Approved symbol	ARHGAP21
Name	Rho GTPase activating protein 21
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1424, ARHGAP10
Ensembl gene	ENSG00000107863
Ensembl biotype	protein_coding
OMIM	609870
Entrez	57584

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000376410, ENST00000396432, ENST00000416305, ENST00000418033, ENST00000418325, ENST00000446003, ENST00000463892, ENST00000472150, ENST00000476067, ENST00000476499, ENST00000477190, ENST00000482792, ENST00000483114, ENST00000486374, ENST00000493154, ENST00000612832, ENST00000636789, ENST00000638156, ENST00000680286, ENST00000903505, ENST00000958435, ENST00000958436, ENST00000958437, ENST00000958438

RefSeq mRNA: 10 — MANE Select: NM_020824 NM_001367447, NM_001367448, NM_001367449, NM_001367450, NM_001367451, NM_001367452, NM_001367453, NM_001367454, NM_001367455, NM_020824

CCDS: CCDS7144, CCDS91222

Canonical transcript exons

ENST00000396432 — 26 exons

Exon	Start	End
ENSE00000694497	24595888	24596043
ENSE00000694533	24596740	24596882
ENSE00001137219	24622733	24622762
ENSE00001137224	24629996	24630050
ENSE00003458482	24591887	24592012
ENSE00003502480	24666985	24667009
ENSE00003507880	24604312	24604348
ENSE00003510929	24594950	24595039
ENSE00003511245	24721837	24722279
ENSE00003515549	24633402	24633480
ENSE00003516980	24595717	24595795
ENSE00003527442	24591225	24591330
ENSE00003543707	24597945	24598009
ENSE00003549041	24589271	24589302
ENSE00003552406	24670218	24670397
ENSE00003580586	24607499	24607601
ENSE00003616527	24635011	24635103
ENSE00003620622	24591642	24591683
ENSE00003623308	24619473	24621369
ENSE00003637620	24601978	24602103
ENSE00003641282	24607745	24607903
ENSE00003647189	24595117	24595190
ENSE00003654098	24597447	24597583
ENSE00003672848	24600646	24600930
ENSE00003841524	24583614	24586106
ENSE00003842920	24723562	24723887

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7952 / max 488.4674, expressed in 1803 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108702	13.4285	1733
108703	7.8364	1703
108699	1.4913	506
108697	0.9416	543
108689	0.8997	124
108701	0.8710	528
108696	0.4400	163
108698	0.3650	164
108695	0.1770	70
108690	0.1262	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.30	gold quality
cerebellar hemisphere	UBERON:0002245	99.19	gold quality
cerebellar cortex	UBERON:0002129	99.11	gold quality
ventricular zone	UBERON:0003053	99.08	gold quality
ganglionic eminence	UBERON:0004023	98.96	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.93	gold quality
right frontal lobe	UBERON:0002810	98.66	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.28	gold quality
calcaneal tendon	UBERON:0003701	98.02	gold quality
cortical plate	UBERON:0005343	97.83	gold quality
spinal cord	UBERON:0002240	97.76	gold quality
adrenal tissue	UBERON:0018303	97.76	gold quality
cerebellum	UBERON:0002037	97.73	gold quality
anterior cingulate cortex	UBERON:0009835	97.56	gold quality
stromal cell of endometrium	CL:0002255	97.39	gold quality
prefrontal cortex	UBERON:0000451	97.08	gold quality
left ovary	UBERON:0002119	97.03	gold quality
amygdala	UBERON:0001876	96.99	gold quality
right ovary	UBERON:0002118	96.84	gold quality
hypothalamus	UBERON:0001898	96.83	gold quality
corpus callosum	UBERON:0002336	96.80	gold quality
putamen	UBERON:0001874	96.60	gold quality
colonic epithelium	UBERON:0000397	96.45	gold quality
nucleus accumbens	UBERON:0001882	96.12	gold quality
caudate nucleus	UBERON:0001873	95.98	gold quality
right coronary artery	UBERON:0001625	95.94	gold quality
sural nerve	UBERON:0015488	95.91	gold quality
body of uterus	UBERON:0009853	95.84	gold quality
endocervix	UBERON:0000458	95.61	gold quality
left uterine tube	UBERON:0001303	95.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	53.15
E-ANND-3	yes	11.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

158 targeting ARHGAP21, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-206	99.93	72.50	1893

Literature-anchored findings (GeneRIF, showing 16)

• ARHGAP10 gene is highly expressed in muscle and brain, which are highly differentiated tissues. It supports the hypothesis that ARHGAP10 is important for cell differentiation (PMID:12056806)
• The ARHGAP10 protein is a novel Rho GTPase-activating protein (Rho-GAP) that is recruited to Golgi membranes through binding to GTP-ARF1. (PMID:15793564)
• The crystal structure of the activated GTP-bound form of ARF1 in a complex with the Arf-binding domain (ArfBD) of ARHGAP21 at 2.1 A resolution, is presented. (PMID:17347647)
• Data demonstrate that the RhoGTPase activating protein 21 (ARHGAP21) is expressed in the nuclear and perinuclear regions of several cell lines, and interacts with the C-terminal region of focal adhesion kinase. (PMID:19268501)
• Disruption of the beta-arrestin 1/ARHGAP21 complex results in a more active ARHGAP21, leading to less efficient signaling via the angiotensin II type 1A receptor and, thereby, attenuation of stimulated stress fiber formation. (PMID:21173159)
• silencing Cdc42 reduced influenza A virus replication, whereas silencing ARHGAP21 increased the virus replication. (PMID:22318733)
• Co-immunoprecipitations and in vitro SUMOylation confirmed ARHGAP21 specific modification by SUMO2/3 and mapped the SUMOylation site to ARHGAP21 lysine K1443. (PMID:22922005)
• ARHGAP21 is a Rho-GAP involved in cell-cell junction remodeling that affects migration and EMT through alpha-tubulin interaction and acetylation (PMID:23235160)
• Gly1121Ser variant in ARHGAP21 gene found to be shared by all MP individuals in arger branch of family with nearly complete penetrance. ARHGAP21 protein strengthens cell-cell adhesions; may be regulated by BMPs influencing mandibular growth. (PMID:25691070)
• The results show that PTEN controls multicellular assembly through a membrane-associated regulatory protein complex composed of beta-Arrestin1, ARHGAP21 and Cdc42. (PMID:28749339)
• Reduced Arhgap21 is associated with Hematopoietic defects. (PMID:29212046)
• In this paper, we aimed to review the available literature regarding ARHGAP21 to highlight its importance and the mechanisms of action that have been found so far for this still unknown protein involved with cell adhesion, migration, Golgi regulation, cell trafficking, and even insulin secretion. (PMID:29856495)
• Deficiency of ARHGAP21 alters megakaryocytic cell lineage responses and enhances platelet hemostatic function. (PMID:33727037)
• ARHGAP21 Is Involved in the Carcinogenic Mechanism of Cholangiocarcinoma: A Study Based on Bioinformatic Analyses and Experimental Validation. (PMID:36676763)
• Silencing of ARHGAP21, a Rho GTPase activating protein (RhoGAP), reduces the growth of prostate cancer xenografts in NOD/SCID mice. (PMID:36764390)
• [ARHGAP21 inhibits epithelial-mesenchymal transition by inactivating the WNT signaling pathway in non-small cell lung cancer]. (PMID:37712268)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgap21b	ENSDARG00000075673
danio_rerio	arhgap21a	ENSDARG00000104295
mus_musculus	Arhgap21	ENSMUSG00000036591
rattus_norvegicus	Arhgap21	ENSRNOG00000008659

Paralogs (1): ARHGAP23 (ENSG00000275832)

Protein

Protein identifiers

Rho GTPase-activating protein 21 — Q5T5U3 (reviewed: Q5T5U3)

Alternative names: Rho GTPase-activating protein 10, Rho-type GTPase-activating protein 21

All UniProt accessions (10): Q5T5U3, A0A087WW76, A0A1B0GTZ9, A0A1B0GV73, A0A7P0TAS2, A0A805TBS0, E7ESW5, H0Y468, H0Y5T2, Q5JSD8

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a GTPase-activating protein (GAP) for RHOA and CDC42. Downstream partner of ARF1 which may control Golgi apparatus structure and function. Also required for CTNNA1 recruitment to adherens junctions.

Subunit / interactions. Interacts with GTP-bound ARF1 and ARF6. Interacts with CTNNA1.

Subcellular location. Golgi apparatus membrane. Cell junction. Cytoplasmic vesicle membrane. Cytoplasm. Cytoskeleton.

Tissue specificity. Widely expressed with higher expression in brain, heart, skeletal muscle and placenta.

Post-translational modifications. Sumoylated with SUMO2 and SUMO3 in proliferating lymphocytes.

Induction. Up-regulated upon cell differentiation.

Miscellaneous. Depletion of ARHGAP21 induces cell spreading and accumulation of F-actin stress fibers. Required for In1A-dependent entry of Listeria monocytogenes into cells.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5T5U3-1	1	yes
Q5T5U3-3	3

RefSeq proteins (10): NP_001354376, NP_001354377, NP_001354378, NP_001354379, NP_001354380, NP_001354381, NP_001354382, NP_001354383, NP_001354384, NP_065875* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001478	PDZ	Domain
IPR001849	PH_domain	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain

Pfam: PF00169, PF00620, PF17820

UniProt features (101 total): modified residue 29, compositionally biased region 19, strand 14, region of interest 13, sequence variant 6, helix 4, sequence conflict 4, domain 3, splice variant 3, mutagenesis site 3, chain 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2J59	X-RAY DIFFRACTION	2.1
2DHJ	SOLUTION NMR
2YUY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T5U3-F1	45.03	0.12

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): 1184 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (30): 36, 57, 459, 554, 575, 612, 616, 625, 717, 747, 857, 862, 881, 882, 924, 926, 954, 1099, 1115, 1418 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
1000	altered interaction with arf1 and loss of association to membranes.
1054	altered interaction with arf1 and loss of association to membranes.
1184	loss of gtpase activity and loss of function.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-9696264	RND3 GTPase cycle

MSigDB gene sets: 374 (showing top): GCM_MAP4K4, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ORGANELLE_TRANSPORT_ALONG_MICROTUBULE, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, BOYLAN_MULTIPLE_MYELOMA_D_DN, GOLDRATH_ANTIGEN_RESPONSE, BOYLAN_MULTIPLE_MYELOMA_D_CLUSTER_DN, GOBP_MAINTENANCE_OF_LOCATION, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, WTGAAAT_UNKNOWN, TGTGTGA_MIR377, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, PPAR_DR1_Q2

GO Biological Process (7): Golgi organization (GO:0007030), signal transduction (GO:0007165), regulation of small GTPase mediated signal transduction (GO:0051056), Golgi localization (GO:0051645), establishment of Golgi localization (GO:0051683), maintenance of Golgi location (GO:0051684), organelle transport along microtubule (GO:0072384)

GO Molecular Function (2): GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), cell junction (GO:0030054), cytoplasmic vesicle membrane (GO:0030659), anchoring junction (GO:0070161), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	13

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
Golgi localization	2
establishment of organelle localization	2
organelle organization	1
endomembrane system organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
organelle localization	1
establishment of localization in cell	1
maintenance of organelle location	1
transport along microtubule	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cytoskeleton	1
vesicle membrane	1
cytoplasmic vesicle	1
cell junction	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
vacuole	1
plasma membrane	1
intracellular vesicle	1

Protein interactions and networks

STRING

1042 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP21	ARF1	P10947	846
ARHGAP21	PRICKLE1	Q96MT3	757
ARHGAP21	PRICKLE3	O43900	678
ARHGAP21	RASA1	P20936	671
ARHGAP21	CDC42	P21181	638
ARHGAP21	PRICKLE4	Q2TBC4	628
ARHGAP21	CDH1	P12830	593
ARHGAP21	RHOA	P06749	557
ARHGAP21	CTNNA1	P35221	553
ARHGAP21	PLEK2	Q9NYT0	538
ARHGAP21	PLEK	P08567	526
ARHGAP21	PRICKLE2	Q7Z3G6	514
ARHGAP21	CCDC85C	A6NKD9	506
ARHGAP21	CTNNB1	P35222	498
ARHGAP21	ARF6	P26438	491

IntAct

487 interactions, top by confidence:

A	B	Type	Score
CTNNB1	AXIN1	psi-mi:“MI:0914”(association)	0.940
CDH1	CTNND1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
CTNNB1	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.590
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
MAP4K4	STRN	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
ARHGAP21	EEF1D	psi-mi:“MI:0915”(physical association)	0.520
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
E6	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP21	NRXN3	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP21	E6	psi-mi:“MI:0407”(direct interaction)	0.440
GP1	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP21	YAP1	psi-mi:“MI:0407”(direct interaction)	0.440
WWTR1	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (239): ARHGAP21 (Two-hybrid), ARHGAP21 (Affinity Capture-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Proximity Label-MS), ARHGAP21 (Affinity Capture-MS), ARHGAP21 (Affinity Capture-MS), ARHGAP21 (Affinity Capture-MS), ARHGAP21 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LFM6, A0A1B0GVH6, A0A1L8H8C0, A0A2K1JJ00, A0JMD2, A2ARZ3, A2AWL7, A4IGV6, A6H5Y1, D3ZJ47, E9Q309, F1QPR4, F5H4B4, H0WFA5, O14513, O35413, O94875, P0CAX8, P48437, Q12912, Q15468, Q1LXZ9, Q1X8D7, Q28FG2, Q3UTJ2, Q3ZBS1, Q499E5, Q49A88, Q4V7H1, Q5T5U3, Q5VT06, Q62417, Q62770, Q69Z38, Q6DFB0, Q80TY4, Q8BLN6, Q8CB14, Q8IWI9, Q8K0T7

Diamond homologs: A0A0G2JTR4, A1A4S6, A2AB59, A2RUV4, A4IF90, A4II46, A6QNS3, A6X8Z5, A7KAX9, A7YY57, A8WRJ2, D3ZFJ3, E7EZG2, E7F3F0, F1LXF1, O14559, O94466, P11274, P15882, P30337, P34288, P38339, P46941, P52757, P55194, P81128, P97393, Q03070, Q08DP6, Q10164, Q12979, Q13017, Q15311, Q17QN0, Q20498, Q2M1Z3, Q3TBD2, Q3UIA2, Q52LW3, Q53QZ3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARHGAP21	“down-regulates activity”	RHOA	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 188 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	42.3×	3e-09
Activation of BAD and translocation to mitochondria	7	42.0×	3e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	37.0×	4e-08
Activation of BH3-only proteins	7	27.4×	3e-07
Signaling by Hippo	6	25.7×	5e-06
RHO GTPases activate PKNs	9	22.5×	3e-08
Intrinsic Pathway for Apoptosis	7	16.1×	1e-05
Apoptosis	11	14.6×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
substantia nigra development	6	13.7×	2e-03
intracellular protein localization	10	6.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	411
Likely benign	34
Benign	13

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
4682608	GRCh37/hg19 4q31.23(chr4:148644749-149301795)x1	Pathogenic
687334	GRCh37/hg19 4q31.21-31.23(chr4:146118793-150492144)x1	Pathogenic
152886	GRCh38/hg38 4q31.23(chr4:147920951-148356485)x1	Likely pathogenic
402147	NM_020824.4(ARHGAP21):c.3491T>G (p.Ile1164Arg)	Likely pathogenic
562975	GRCh37/hg19 4q31.23(chr4:148916436-149103774)x1	Likely pathogenic
997080	GRCh37/hg19 4q31.23(chr4:148911418-149103259)	Likely pathogenic

SpliceAI

11015 predictions. Top by Δscore:

Variant	Effect	Δscore
10:24589267:TTAC:T	donor_loss	1.0000
10:24589268:TACCT:T	donor_loss	1.0000
10:24589270:CCTTA:C	donor_loss	1.0000
10:24589303:C:CC	acceptor_gain	1.0000
10:24591640:A:AC	donor_gain	1.0000
10:24591641:C:CC	donor_gain	1.0000
10:24591885:A:AC	donor_gain	1.0000
10:24591886:C:CC	donor_gain	1.0000
10:24591886:CGTG:C	donor_gain	1.0000
10:24592012:TCTG:T	acceptor_loss	1.0000
10:24592013:CTGA:C	acceptor_loss	1.0000
10:24592014:T:C	acceptor_loss	1.0000
10:24594946:ATACC:A	donor_loss	1.0000
10:24594947:TA:T	donor_loss	1.0000
10:24594948:A:AC	donor_gain	1.0000
10:24594948:A:T	donor_loss	1.0000
10:24594949:C:CC	donor_gain	1.0000
10:24594949:CCTTA:C	donor_gain	1.0000
10:24595039:TC:T	acceptor_loss	1.0000
10:24595040:C:CA	acceptor_loss	1.0000
10:24595040:C:CC	acceptor_gain	1.0000
10:24595041:T:G	acceptor_loss	1.0000
10:24595115:A:AC	donor_gain	1.0000
10:24595116:C:CC	donor_gain	1.0000
10:24595116:CTAGT:C	donor_gain	1.0000
10:24595186:TTTAT:T	acceptor_gain	1.0000
10:24595191:C:CC	acceptor_gain	1.0000
10:24595842:C:CT	acceptor_gain	1.0000
10:24595843:A:T	acceptor_gain	1.0000
10:24595881:AACTT:A	donor_loss	1.0000

AlphaMissense

12815 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:24591272:A:G	L1368S	1.000
10:24591897:A:G	L1331P	1.000
10:24591897:A:T	L1331H	1.000
10:24591927:A:G	M1321T	1.000
10:24591969:A:T	V1307D	1.000
10:24591972:A:G	L1306P	1.000
10:24591972:A:T	L1306H	1.000
10:24591978:G:C	P1304R	1.000
10:24591978:G:T	P1304H	1.000
10:24591981:C:T	G1303D	1.000
10:24591982:C:A	G1303C	1.000
10:24591982:C:G	G1303R	1.000
10:24591987:A:T	V1301E	1.000
10:24591990:A:C	I1300R	1.000
10:24591990:A:T	I1300K	1.000
10:24591993:G:A	A1299V	1.000
10:24591993:G:T	A1299E	1.000
10:24591996:A:G	L1298P	1.000
10:24591996:A:T	L1298Q	1.000
10:24591998:G:C	N1297K	1.000
10:24591998:G:T	N1297K	1.000
10:24592011:A:C	M1293R	1.000
10:24592011:A:G	M1293T	1.000
10:24592011:A:T	M1293K	1.000
10:24594953:A:C	N1291K	1.000
10:24594953:A:T	N1291K	1.000
10:24594973:C:G	A1285P	1.000
10:24594984:A:G	L1281P	1.000
10:24594988:G:C	H1280D	1.000
10:24594996:A:G	L1277P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002525 (10:24724156 C>A,G), RS1000048373 (10:24583337 T>C), RS1000052583 (10:24631369 A>G), RS1000071913 (10:24617528 G>T), RS1000112203 (10:24718472 C>T), RS1000125554 (10:24646620 A>G), RS1000144886 (10:24634078 G>A), RS1000161542 (10:24703770 G>A,C), RS1000188612 (10:24649996 T>C), RS1000195388 (10:24712993 G>A), RS1000201846 (10:24599206 C>G,T), RS1000206204 (10:24677833 T>G), RS1000240968 (10:24650433 T>C), RS1000243110 (10:24695153 T>C), RS1000255084 (10:24646563 G>C)

Disease associations

OMIM: gene MIM:609870 | disease phenotypes: MIM:616487

GenCC curated gene-disease

Mondo (3): epidermolysis bullosa simplex with nail dystrophy (MONDO:0014661), intellectual disability (MONDO:0001071), pseudohypoaldosteronism (MONDO:0018638)

Orphanet (2): Pseudohypoaldosteronism (Orphanet:444916), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000452_3	QT interval	7.000000e-07
GCST001537_8	Immune reponse to smallpox (secreted IL-12p40)	1.000000e-08
GCST002875_1	Diisocyanate-induced asthma	5.000000e-06
GCST003219_3	Advanced age-related macular degeneration	4.000000e-08
GCST003818_77	Resting heart rate	2.000000e-14
GCST005192_150	Lobe attachment (rater-scored or self-reported)	9.000000e-68
GCST005193_1	Lobe attachment (rater scored)	2.000000e-08
GCST006061_104	Atrial fibrillation	7.000000e-13
GCST006061_106	Atrial fibrillation	6.000000e-14
GCST006414_88	Atrial fibrillation	1.000000e-11
GCST008362_192	Birth weight	4.000000e-09
GCST008508_5	Stress sensitivity (neuroticism score x major depressive disorder status interaction)	4.000000e-06
GCST009411_8	Optic disc area	2.000000e-08
GCST009462_103	Optic disc size	9.000000e-13
GCST009615_10	Triglyceride levels x loop diuretics use interaction	1.000000e-08
GCST009615_9	Triglyceride levels x loop diuretics use interaction	7.000000e-07
GCST010083_18	Hemoglobin levels	1.000000e-11
GCST010566_5	Benign childhood epilepsy with centro-temporal spikes	9.000000e-06
GCST90000025_393	Appendicular lean mass	8.000000e-14
GCST90002383_398	Hematocrit	5.000000e-13
GCST90002384_146	Hemoglobin	8.000000e-13
GCST90002387_349	Immature fraction of reticulocytes	2.000000e-11
GCST90011900_92	Serum alkaline phosphatase levels	1.000000e-28
GCST90013406_225	Liver enzyme levels (alkaline phosphatase)	2.000000e-43

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0006995	response to diisocyanate
EFO:1001492	atrophic macular degeneration
EFO:0007667	lobe attachment
EFO:0004344	birth weight
EFO:0007660	neuroticism measurement
EFO:0004530	triglyceride measurement
EFO:0004509	hemoglobin measurement
EFO:0004980	appendicular lean mass
EFO:0004348	hematocrit
EFO:0004533	alkaline phosphatase measurement

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
D011546	Pseudohypoaldosteronism	C12.050.351.968.419.815.770; C12.200.777.419.815.770; C12.950.419.815.770; C16.320.831.770

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
bisphenol A	affects expression, decreases methylation	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
arsenite	decreases reaction, affects binding	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
coumarin	affects phosphorylation	1
methacrylaldehyde	increases oxidation, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
monomethylarsonous acid	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	affects cotreatment, increases oxidation	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	increases mutagenesis	1
Cacodylic Acid	increases expression	1
Caffeine	affects phosphorylation	1
Formaldehyde	decreases expression	1
Mustard Gas	increases phosphorylation	1
Ozone	affects cotreatment, increases oxidation	1
Quercetin	decreases phosphorylation	1
Thiram	increases expression	1

Clinical trials (associated diseases)

202 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
NCT00004328	PHASE2	COMPLETED	Phase II Study of the Pathophysiology and Treatment With Enalapril and Polystyrene Sulfonate for Pseudohypoaldosteronism, Type I
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