ARHGAP26

Summary

ARHGAP26 (Rho GTPase activating protein 26, HGNC:17073) is a protein-coding gene on chromosome 5q31.3, encoding Rho GTPase-activating protein 26 (Q9UNA1). GTPase-activating protein for RHOA and CDC42.

Interaction of a cell with the extracellular matrix triggers integrin cell surface receptors to begin signaling cascades that regulate the organization of the actin-cytoskeleton. One of the proteins involved in these cascades is focal adhesion kinase. The protein encoded by this gene is a GTPase activating protein that binds to focal adhesion kinase and mediates the activity of the GTP binding proteins RhoA and Cdc42. Defects in this gene are a cause of juvenile myelomonocytic leukemia (JMML). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23092 — RefSeq curated summary.

At a glance

• Gene–disease (curated): juvenile myelomonocytic leukemia (No Known Disease Relationship, GenCC)
• GWAS associations: 25
• Clinical variants (ClinVar): 130 total — 3 pathogenic
• Phenotypes (HPO): 3
• MANE Select transcript: NM_001135608

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17073
Approved symbol	ARHGAP26
Name	Rho GTPase activating protein 26
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	GRAF, KIAA0621, OPHN1L, OPHN1L1
Ensembl gene	ENSG00000145819
Ensembl biotype	protein_coding
OMIM	605370
Entrez	23092

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 11 protein_coding, 8 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000274498, ENST00000378013, ENST00000418236, ENST00000419676, ENST00000421521, ENST00000424007, ENST00000425417, ENST00000443045, ENST00000443674, ENST00000451259, ENST00000461314, ENST00000464838, ENST00000469131, ENST00000469396, ENST00000470032, ENST00000475287, ENST00000477867, ENST00000486650, ENST00000489924, ENST00000642734, ENST00000645625, ENST00000645722, ENST00000646213

RefSeq mRNA: 3 — MANE Select: NM_001135608 NM_001135608, NM_001349547, NM_015071

CCDS: CCDS4277, CCDS47297, CCDS87332

Canonical transcript exons

ENST00000645722 — 23 exons

Exon	Start	End
ENSE00001648693	142875110	142875171
ENSE00001663634	143133967	143134105
ENSE00001684142	143056028	143056086
ENSE00001753526	142873400	142873495
ENSE00001754298	142901935	142902039
ENSE00001761707	143057642	143057747
ENSE00001769868	143207198	143207308
ENSE00001921830	142770377	142770915
ENSE00002061033	143147231	143147381
ENSE00002527333	143120988	143121147
ENSE00003504151	142903540	142903669
ENSE00003527568	142885298	142885399
ENSE00003530049	142894238	142894348
ENSE00003534889	143037196	143037261
ENSE00003541883	143041816	143041890
ENSE00003557690	142932047	142932125
ENSE00003560455	143213997	143214088
ENSE00003595866	142907704	142907804
ENSE00003606305	143014080	143014116
ENSE00003613473	143054439	143054526
ENSE00003660609	142879374	142879445
ENSE00003681488	142913199	142913293
ENSE00003842834	143222358	143229007

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 97.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.6154 / max 1636.2291, expressed in 1645 samples.

FANTOM5 promoters (27 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59091	8.7653	1331
59090	7.8899	1234
59092	1.4522	428
59089	1.2994	580
59143	0.8573	255
59097	0.5019	183
59095	0.4907	171
59094	0.4088	177
59096	0.1711	66
59093	0.1583	70

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.81	gold quality
blood	UBERON:0000178	96.15	gold quality
colonic epithelium	UBERON:0000397	95.71	gold quality
monocyte	CL:0000576	93.40	gold quality
mononuclear cell	CL:0000842	93.32	gold quality
leukocyte	CL:0000738	93.20	gold quality
right uterine tube	UBERON:0001302	91.90	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.07	gold quality
granulocyte	CL:0000094	90.22	gold quality
bone marrow cell	CL:0002092	89.98	gold quality
calcaneal tendon	UBERON:0003701	89.40	gold quality
postcentral gyrus	UBERON:0002581	89.07	gold quality
parietal lobe	UBERON:0001872	88.85	gold quality
tonsil	UBERON:0002372	88.81	gold quality
left testis	UBERON:0004533	88.16	gold quality
superior frontal gyrus	UBERON:0002661	87.97	gold quality
corpus callosum	UBERON:0002336	87.95	gold quality
gall bladder	UBERON:0002110	87.56	gold quality
right testis	UBERON:0004534	87.51	gold quality
right lung	UBERON:0002167	87.46	gold quality
testis	UBERON:0000473	87.22	gold quality
upper lobe of left lung	UBERON:0008952	86.75	gold quality
prefrontal cortex	UBERON:0000451	86.72	gold quality
cerebellum	UBERON:0002037	86.57	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.54	gold quality
cerebellar cortex	UBERON:0002129	86.53	gold quality
cerebellar hemisphere	UBERON:0002245	86.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.34	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.25	gold quality
right atrium auricular region	UBERON:0006631	86.22	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	3420.40
E-CURD-119	yes	2870.77
E-GEOD-111727	yes	628.74
E-HCAD-35	yes	43.92
E-HCAD-25	yes	21.73
E-MTAB-7606	no	676.85
E-HCAD-30	no	570.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

207 targeting ARHGAP26, 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-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-548AE-3P	99.93	72.66	4867

Literature-anchored findings (GeneRIF, showing 23)

• Graf residues important for the structural integrity are critical for binding RhoA and for the catalytic activity of GAP, but GTPase selectivity appears to be modulated by a more subtle interplay involving residues on the periphery of the main interface. (PMID:18929667)
• abnormal GRAF methylation might be an adverse prognostic event in MDS (PMID:20374274)
• The GRAF gene was down-regulated in AML, which might play a role in the leukemogenesis. (PMID:20533268)
• The analysis of the expression pattern of the GRAF1/OPHN-1-L gene in human tissues and organs revealed the predominant brain expression of a novel splicing isoform. (PMID:20602808)
• Decreased level of GRAF transcript is associated with acute myeloid leukemia, myelodysplastic syndrome and chronic myeloid leukemia. (PMID:20704716)
• Findings suggest that the hypermethylation of GRAF promoter might be one of early events in the development of AML. (PMID:21074269)
• a GTPase-activating protein that regulates muscle maturation and to highlight the functional importance of BAR domains in myotube formation (PMID:21622574)
• proposed that GRAF1 remodels membrane microdomains at adhesion sites into endocytic carriers, facilitating membrane turnover during cell morphological changes (PMID:21965292)
• ADAR1 regulates the expression of ARHGAP26 through A-to-I RNA editing by disrupting the binding of miR-30b-3p and miR-573 within the 3’ UTR of ARHGAP26. (PMID:24067935)
• GRAF expression is a favorable prognostic marker in patients with acute myeloid leukemia. (PMID:25088035)
• We conclude that a transient interaction between Cdc42 and GRAF1 drives endocytic turnover and controls the transition essential for endosomal maturation of plasma membrane internalised by this mechanism. (PMID:26446261)
• GRAF1 plays a role in the maintenance of normal epithelial phenotype and its depletion leads to an epithelial-mesenchymal transition-like process that might be involved in neoplastic transformation. (PMID:27588930)
• High ARHGAP26 expression is associated with adenomyosis. (PMID:30387365)
• Data indicate that hypoxia-induced Rho GTPase activating protein 26 (ARHGAP26) deficiency inhibits ductus arteriosus smooth muscle cells (DASMCs) proliferation and migration through activating the RhoA-ROCK-PTEN pathway. (PMID:30592323)
• This study showed that the circARHGAP26 is overexpressed and its downregulation inhibits cell proliferation and promotes cells apoptosis in GC cells. (PMID:30719998)
• ARHGAP26 upregulation in SKOV3 cells significantly inhibited SMURF1 upregulation-induced cell migration and invasion. Overall, SMURF1-mediated ubiquitination of ARHGAP26 may promote invasion and migration of ovarian cancer cells via the beta-catenin pathway. (PMID:31004081)
• The role of GTPase-activating protein ARHGAP26 in human cancers. (PMID:34716859)
• Associations of ARHGAP26 Polymorphisms with Alzheimer’s Disease and Cardiovascular Disease. (PMID:35171450)
• Missense Variants in GFRA1 and NPNT Are Associated with Congenital Anomalies of the Kidney and Urinary Tract. (PMID:36292572)
• CEMIP, acting as a scaffold protein for bridging GRAF1 and MIB1, promotes colorectal cancer metastasis via activating CDC42/MAPK pathway. (PMID:36849460)
• GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis. (PMID:38081847)
• ARHGAP26/GRAF1 orchestrates actin remodeling and membrane dynamics to drive mitochondrial clearance and promote fuel flexibility. (PMID:38855880)
• GRAF is a negative regulator of RhoA in vivo, it acts as a GTP-ase activating protein (GAP) for RhoA and may be a downstream effector of RhoA in certain cell types. (PMID:9858476)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Arhgap26	ENSMUSG00000036452
rattus_norvegicus	Arhgap26	ENSRNOG00000013920

Paralogs (3): ARHGAP10 (ENSG00000071205), OPHN1 (ENSG00000079482), ARHGAP42 (ENSG00000165895)

Protein

Protein identifiers

Rho GTPase-activating protein 26 — Q9UNA1 (reviewed: Q9UNA1)

Alternative names: GTPase regulator associated with focal adhesion kinase, Oligophrenin-1-like protein, Rho-type GTPase-activating protein 26

All UniProt accessions (13): A0A0S2Z536, A0A2R8Y5C0, A0A2R8YDK5, A0A2R8YGB3, C9J6V4, Q9UNA1, H0Y4P9, H0Y835, H7BZE1, H7BZZ0, H7C1J1, H7C205, H7C3P8

UniProt curated annotations — full annotation on UniProt →

Function. GTPase-activating protein for RHOA and CDC42. Facilitates mitochondrial quality control by promoting Parkin-mediated recruitment of autophagosomes to damaged mitochondria. Negatively regulates the growth of human parainfluenza virus type 2 by inhibiting hPIV-2-mediated RHOA activation via interaction with two of its viral proteins P and V. Associates with MICAL1 on the endosomal membrane to promote Rab8-Rab10-dependent tubule extension. After dissociation of MICAL1, recruits WDR44 which connects the endoplasmic reticulum (ER) with the endosomal tubule, thereby participating in the export of a subset of neosynthesized proteins.

Subunit / interactions. Interacts with NYAP1, NYAP2 and MYO16. Interacts with MICAL1 and WDR44. Binds to the C-terminus of PTK2/FAK1. (Microbial infection) Interacts with human parainfluenza virus type 2 proteins P and V.

Subcellular location. Endosome membrane Cytoplasm. Cell junction. Focal adhesion. Cytoplasm. Cytoskeleton.

Post-translational modifications. Phosphorylated in a PINK1-dependent fashion promoting retrograde mitochondrial trafficking and clustering.

Disease relevance. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785] An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. The gene represented in this entry is involved in disease pathogenesis. A chromosomal translocation t(5;11)(q31;q23) with KMT2A/MLL1 has been found in leukemic cells from JMML patients, also carrying inactivating mutations on the second allele.

Domain organisation. The BAR domain is important to associate RAB8A (or RAB8B) and RAB10 to endosomal membrane to promote tubule extension. The BAR domain is also important to recruit WDR44 to endosomal tubules.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UNA1-1	1	yes
Q9UNA1-2	2, GRAF1b

RefSeq proteins (3): NP_001129080, NP_001336476, NP_055886 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001452	SH3_domain	Domain
IPR001849	PH_domain	Domain
IPR004148	BAR_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR035481	GRAF_SH3	Domain
IPR035483	GRAF_BAR	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR047225	PH_GRAF	Domain
IPR047234	GRAF_fam	Family

Pfam: PF00169, PF00620, PF14604, PF16746

UniProt features (25 total): strand 6, domain 4, modified residue 3, compositionally biased region 3, mutagenesis site 2, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, helix 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1UGV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNA1-F1	78.09	0.58

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

Post-translational modifications (3): 668, 670, 671

Mutagenesis-validated functional residues (2):

Position	Phenotype
668	significantly reduced pink1-mediated phosphorylation.
671	significantly reduced pink1-mediated phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

10 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-9013409	RHOJ GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle

MSigDB gene sets: 315 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, PEREZ_TP63_TARGETS, AREB6_03, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, MEF2_02, GGGTGGRR_PAX4_03, BOYLAN_MULTIPLE_MYELOMA_D_DN, RODRIGUES_NTN1_TARGETS_DN, GOBP_MACROAUTOPHAGY, MAYBURD_RESPONSE_TO_L663536_UP, MODULE_331, FOSTER_TOLERANT_MACROPHAGE_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GTGTTGA_MIR505, GATA1_03

GO Biological Process (4): mitophagy (GO:0000423), signal transduction (GO:0007165), actin cytoskeleton organization (GO:0030036), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (4): GTPase activator activity (GO:0005096), phospholipid binding (GO:0005543), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (9): mitochondrion (GO:0005739), cytosol (GO:0005829), cytoskeleton (GO:0005856), focal adhesion (GO:0005925), endosome membrane (GO:0010008), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	10

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
autophagy of mitochondrion	1
macroautophagy	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cytoskeleton organization	1
actin filament-based process	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
lipid binding	1
protein binding	1
molecular adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
cell-substrate junction	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
intracellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1
cell junction	1

Protein interactions and networks

STRING

1050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGAP26	PKN3	Q6P5Z2	895
ARHGAP26	DNER	Q8NFT8	738
ARHGAP26	AMPH	P49418	729
ARHGAP26	RHOA	P06749	727
ARHGAP26	CLDN18	P56856	708
ARHGAP26	BIN1	O00499	676
ARHGAP26	ITPR1	Q14643	651
ARHGAP26	RASA1	P20936	638
ARHGAP26	KRAS	P01116	624
ARHGAP26	HOMER3	Q9NSC5	602
ARHGAP26	RCVRN	P35243	595
ARHGAP26	EHD1	Q9H4M9	592
ARHGAP26	ZIC4	Q8N9L1	580
ARHGAP26	CNTNAP1	P78357	577
ARHGAP26	ILK	P57043	573

IntAct

27 interactions, top by confidence:

A	B	Type	Score
PKN3	ARHGAP26	psi-mi:“MI:0915”(physical association)	0.680
ARHGAP26	PKN3	psi-mi:“MI:0915”(physical association)	0.680
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
CDC42EP2	ARHGAP26	psi-mi:“MI:0915”(physical association)	0.560
ARHGAP26	CDC42EP2	psi-mi:“MI:0915”(physical association)	0.560
COLEC12	CSPG5	psi-mi:“MI:0914”(association)	0.530
TULP1	NRXN1	psi-mi:“MI:0914”(association)	0.510
ARHGAP26	ARHGAP10	psi-mi:“MI:0914”(association)	0.510
ARHGAP26	SRPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ARHGAP26	apc	psi-mi:“MI:0407”(direct interaction)	0.440
Nyap1	ARHGAP26	psi-mi:“MI:0915”(physical association)	0.400
ARHGAP26	Nyap2	psi-mi:“MI:0915”(physical association)	0.400
MYO16	ARHGAP26	psi-mi:“MI:0915”(physical association)	0.400
C2CD2	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
NHSL3	ASAP2	psi-mi:“MI:0914”(association)	0.350
ANKS1B	MCC	psi-mi:“MI:0914”(association)	0.350
ARHGAP26	ARHGAP10	psi-mi:“MI:0915”(physical association)	0.000
ARHGAP26	TULP1	psi-mi:“MI:0915”(physical association)	0.000
ARHGAP26	CTR9	psi-mi:“MI:0915”(physical association)	0.000
ELOA	ARHGAP26	psi-mi:“MI:0915”(physical association)	0.000
NRXN1	ARHGAP26	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (88): ARHGAP26 (Two-hybrid), ARHGAP26 (Affinity Capture-MS), ACADS (Co-fractionation), ARHGAP26 (Two-hybrid), ARHGAP42 (Affinity Capture-MS), OPHN1 (Affinity Capture-MS), ARHGAP10 (Affinity Capture-MS), ARHGAP26 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), JPH1 (Affinity Capture-MS), RAB11FIP5 (Affinity Capture-MS), ARHGAP26 (Affinity Capture-Western), ARHGAP26 (Affinity Capture-Western), ARHGAP26 (Affinity Capture-Western), ARHGAP26 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTR4, A1A4S6, A2AWA9, A4FUD6, A4II46, A6H6A9, A6QNS3, A6QQZ7, O60890, P09851, P0CAX5, P20936, P23727, P26450, P27986, P50904, Q08DP6, Q12979, Q5R372, Q5R5M3, Q5R685, Q5R6F2, Q5R8I6, Q5RCC1, Q5RCW6, Q5SSL4, Q5T2T1, Q5U2Y3, Q5ZJ17, Q5ZLX4, Q5ZMW5, Q62696, Q63787, Q6Y5D8, Q6ZQ82, Q7YQL5, Q7YQL6, Q8AVG0, Q8BPU7, Q8K0F1

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

5 interactions.

A	Effect	B	Mechanism
ARHGAP26	“down-regulates activity”	RHOA	“gtpase-activating protein”
MAPK1	unknown	ARHGAP26	phosphorylation
MAPK3	unknown	ARHGAP26	phosphorylation
Gbeta	unknown	ARHGAP26	phosphorylation
ERK1/2	unknown	ARHGAP26	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	70
Likely benign	10
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3062812	GRCh37/hg19 5q31.3-32(chr5:141566629-147240595)x1	Pathogenic
5053	ARHGAP26, 52-BP INS	Pathogenic
5054	ARHGAP26, 74-BP INS	Pathogenic

SpliceAI

6450 predictions. Top by Δscore:

Variant	Effect	Δscore
5:142770885:G:GT	donor_gain	1.0000
5:142770890:G:GT	donor_gain	1.0000
5:142770890:G:T	donor_gain	1.0000
5:142770912:AAGAG:A	donor_loss	1.0000
5:142770913:AGA:A	donor_gain	1.0000
5:142770913:AGAG:A	donor_loss	1.0000
5:142770914:GA:G	donor_gain	1.0000
5:142770914:GAG:G	donor_gain	1.0000
5:142770914:GAGT:G	donor_loss	1.0000
5:142770915:AGTGA:A	donor_loss	1.0000
5:142770916:G:C	donor_loss	1.0000
5:142770916:G:GG	donor_gain	1.0000
5:142770917:T:A	donor_loss	1.0000
5:142770918:GAGTG:G	donor_loss	1.0000
5:142780295:A:G	acceptor_gain	1.0000
5:142873395:GCTA:G	acceptor_loss	1.0000
5:142873397:TAG:T	acceptor_loss	1.0000
5:142873398:A:AG	acceptor_gain	1.0000
5:142873399:G:GA	acceptor_loss	1.0000
5:142873399:G:GG	acceptor_gain	1.0000
5:142873399:GA:G	acceptor_gain	1.0000
5:142873399:GAT:G	acceptor_gain	1.0000
5:142873399:GATT:G	acceptor_gain	1.0000
5:142873399:GATTT:G	acceptor_gain	1.0000
5:142875108:A:AG	acceptor_gain	1.0000
5:142875109:G:GG	acceptor_gain	1.0000
5:142875109:GCAA:G	acceptor_gain	1.0000
5:142875167:GGATG:G	donor_gain	1.0000
5:142875168:GATGG:G	donor_gain	1.0000
5:142879354:A:AG	acceptor_gain	1.0000

AlphaMissense

5054 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:142770778:T:A	L6H	1.000
5:142770783:T:C	F8L	1.000
5:142770784:T:C	F8S	1.000
5:142770784:T:G	F8C	1.000
5:142770785:C:A	F8L	1.000
5:142770785:C:G	F8L	1.000
5:142770817:G:C	R19P	1.000
5:142770826:T:C	L22P	1.000
5:142770847:T:C	L29P	1.000
5:142770877:T:C	L39P	1.000
5:142770898:T:C	L46P	1.000
5:142873426:G:C	A61P	1.000
5:142875161:G:C	R101P	1.000
5:142879396:T:C	L112P	1.000
5:142879416:T:C	F119L	1.000
5:142879417:T:C	F119S	1.000
5:142879418:T:A	F119L	1.000
5:142879418:T:G	F119L	1.000
5:142879420:G:C	R120P	1.000
5:142894287:T:C	L179P	1.000
5:142894292:T:C	Y181H	1.000
5:142894296:T:A	V182D	1.000
5:142894331:T:C	F194L	1.000
5:142894333:T:A	F194L	1.000
5:142894333:T:G	F194L	1.000
5:142903583:T:C	L249P	1.000
5:142903652:T:C	L272P	1.000
5:142907721:T:A	W284R	1.000
5:142907721:T:C	W284R	1.000
5:142907742:T:G	Y291D	1.000

dbSNP variants (sampled 300 via entrez): RS1000002821 (5:142902422 G>A,C), RS1000006775 (5:142938572 A>G), RS1000013012 (5:142771470 T>G), RS1000013302 (5:143186138 T>A), RS1000015195 (5:142849196 C>T), RS1000037132 (5:143145564 C>T), RS1000046444 (5:142848987 A>G), RS1000049717 (5:143063409 C>G), RS1000053551 (5:143151938 C>A,T), RS1000065916 (5:143226261 C>T), RS1000075861 (5:143226140 G>A), RS1000076705 (5:142937294 G>A,C), RS1000083835 (5:142852642 A>C), RS1000088755 (5:143162490 A>G), RS1000101808 (5:143098293 C>G,T)

Disease associations

OMIM: gene MIM:605370 | disease phenotypes: MIM:607785

GenCC curated gene-disease

Disease	Classification	Inheritance
juvenile myelomonocytic leukemia	No Known Disease Relationship	Unknown

Mondo (1): juvenile myelomonocytic leukemia (MONDO:0011908)

Orphanet (1): Juvenile myelomonocytic leukemia (Orphanet:86834)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001442	Typified by somatic mosaicism
HP:0012209	Juvenile myelomonocytic leukemia

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST003542_139	Night sleep phenotypes	8.000000e-06
GCST005194_36	Coronary artery disease	2.000000e-17
GCST005195_33	Coronary artery disease	7.000000e-17
GCST005196_89	Coronary artery disease	2.000000e-17
GCST006061_141	Atrial fibrillation	1.000000e-11
GCST006061_142	Atrial fibrillation	6.000000e-11
GCST006288_321	Heel bone mineral density	7.000000e-07
GCST006288_538	Heel bone mineral density	2.000000e-09
GCST006979_124	Heel bone mineral density	1.000000e-23
GCST007096_202	Pulse pressure	2.000000e-09
GCST008151_65	Waist circumference	9.000000e-06
GCST008160_24	Waist circumference	9.000000e-06
GCST008839_313	Height	3.000000e-09
GCST009391_717	Metabolite levels	4.000000e-06
GCST009597_218	Multiple sclerosis	7.000000e-07
GCST010321_138	PR interval	3.000000e-10
GCST011304_3	Septic shock resolution	9.000000e-08
GCST011365_129	Myocardial infarction	1.000000e-06
GCST011741_34	LDL cholesterol levels in HIV infection	7.000000e-06
GCST012279_6	Suicide attempt severity in mood disorders	3.000000e-06
GCST90000025_20	Appendicular lean mass	6.000000e-13
GCST90002381_395	Eosinophil count	4.000000e-15
GCST90002381_396	Eosinophil count	1.000000e-09
GCST90002382_127	Eosinophil percentage of white cells	8.000000e-16
GCST90002382_128	Eosinophil percentage of white cells	4.000000e-11

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0010532	salicylurate measurement
EFO:0004462	PR interval
EFO:0006834	septic shock
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0006882	suicide behaviour measurement
EFO:0004980	appendicular lean mass
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3776332	ARHGAP26		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	8
Benzo(a)pyrene	affects methylation, decreases expression	5
Estradiol	increases expression, increases reaction, affects expression	5
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, affects expression	4
trichostatin A	affects expression, increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Ozone	affects expression, affects cotreatment, increases oxidation, increases abundance	2
Tretinoin	decreases expression, increases expression, affects cotreatment	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
sodium bichromate	decreases expression	1
sulforaphane	increases expression	1
beryllium sulfate	decreases expression, increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
avobenzone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01339988	PHASE4	UNKNOWN	Busulfan and Cyclophosphamide Instead of Total Boby Irradiation (TBI) and Cyclophosphamide for Hematological Malignancies Hematocrit (HCT)
NCT00002798	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
NCT00152139	PHASE3	COMPLETED	Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00186823	PHASE3	COMPLETED	Haploidentical Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00450450	PHASE3	COMPLETED	Donor Bone Marrow Transplant With or Without G-CSF in Treating Young Patients With Hematologic Cancer or Other Diseases
NCT00799461	PHASE3	COMPLETED	Internet-Based Program With or Without Telephone-Based Problem-Solving Training in Helping Long-Term Survivors of Hematopoietic Stem Cell Transplant Cope With Late Complications
NCT00843882	PHASE3	ACTIVE_NOT_RECRUITING	Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
NCT01241500	PHASE3	COMPLETED	Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts
NCT01305200	PHASE3	COMPLETED	Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant
NCT01749111	PHASE3	TERMINATED	Comparison Between Cyclophosphamide and Combination of Methotrexate + Calcineurin Inhibitor for GVHD Prophylaxis
NCT01928537	PHASE3	COMPLETED	Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine
NCT03306264	PHASE3	COMPLETED	Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML
NCT04842604	PHASE3	COMPLETED	Continuation Study of B1371019(NCT03416179) and B1371012(NCT02367456) Evaluating Azacitidine With Or Without Glasdegib In Patients With Previously Untreated AML, MDS or CMML
NCT05515029	PHASE3	ACTIVE_NOT_RECRUITING	Preventing of GVHD With Post-transplantation Cyclophosphamide, Abatacept, Vedolizumab and Calcineurin Inhibitor at Patients With Hemoblastosis
NCT06647862	PHASE3	RECRUITING	IMM01+Azacitidine VS Placebo +Azacitidine in Patients With Newly Diagnosed Chronic Myelomonocytic Leukemia (CMML1-2)
NCT00015990	PHASE2	COMPLETED	Thalidomide in Treating Patients With Myelodysplastic Syndrome
NCT00025038	PHASE2	COMPLETED	Combination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplant in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia
NCT00039416	PHASE2	COMPLETED	Imatinib Mesylate in Treating Patients With Myelofibrosis
NCT00067808	PHASE2	COMPLETED	Study of Three Different Schedules of Low-Dose Decitabine in Myelodysplastic Syndrome (MDS)
NCT00079313	PHASE2	COMPLETED	Imatinib (Gleevec(Registered Trademark)) to Treat Chronic Myelomonocytic Leukemia and Atypical Chronic Myelogenous Leukemia
NCT00084916	PHASE2	COMPLETED	CCI-779 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, or Chronic Myelogenous Leukemia in Blastic Phase
NCT00113321	PHASE2	TERMINATED	Low-Dose Decitabine in Myelodysplastic Syndrome Post Azacytidine Failure
NCT00118352	PHASE2	COMPLETED	Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
NCT00119366	PHASE2	TERMINATED	Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
NCT00136409	PHASE2	COMPLETED	A Study of Gleevec in Patients With Idiopathic Myelofibrosis or Chronic Myelomonocytic Leukemia (CMML)
NCT00143559	PHASE2	COMPLETED	Stem Cell Transplantation as Immunotherapy for Hematologic Malignancies
NCT00145613	PHASE2	COMPLETED	Haploidentical Stem Cell Transplant for Treatment Refractory Hematological Malignancies
NCT00171912	PHASE2	COMPLETED	Imatinib Mesylate in Patients With Various Types of Malignancies Involving Activated Tyrosine Kinase Enzymes
NCT00299156	PHASE2	COMPLETED	Oral Clofarabine Study in Patients With Myelodysplastic Syndrome
NCT00309907	PHASE2	COMPLETED	Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant
NCT00313586	PHASE2	COMPLETED	Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia
NCT00381550	PHASE2	COMPLETED	3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia
NCT00387426	PHASE2	TERMINATED	Sunitinib in Treating Patients With Idiopathic Myelofibrosis
NCT00397813	PHASE2	COMPLETED	Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders
NCT00451048	PHASE2	COMPLETED	Sunitinib in Treating Patients With Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia
NCT00462605	PHASE2	COMPLETED	MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia
NCT00489203	PHASE2	COMPLETED	Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
NCT00509249	PHASE2	TERMINATED	Aflibercept in Treating Patients With Myelodysplastic Syndromes
NCT00566696	PHASE2	COMPLETED	Mismatched Family Member Donor Transplantation for Children and Young Adults With High Risk Hematological Malignancies
NCT00795769	PHASE2	COMPLETED	Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant