ARHGEF18

Summary

ARHGEF18 (Rho/Rac guanine nucleotide exchange factor 18, HGNC:17090) is a protein-coding gene on chromosome 19p13.2, encoding Rho guanine nucleotide exchange factor 18 (Q6ZSZ5). Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPases.

Rho GTPases are GTP binding proteins that regulate a wide spectrum of cellular functions. These cellular processes include cytoskeletal rearrangements, gene transcription, cell growth and motility. Activation of Rho GTPases is under the direct control of guanine nucleotide exchange factors (GEFs). The protein encoded by this gene is a guanine nucleotide exchange factor and belongs to the Rho GTPase GEF family. Family members share a common feature, a Dbl (DH) homology domain followed by a pleckstrin (PH) homology domain. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 23370 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinitis pigmentosa 78 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 1,144 total — 21 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_001367823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17090
Approved symbol	ARHGEF18
Name	Rho/Rac guanine nucleotide exchange factor 18
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	P114-RhoGEF, KIAA0521, MGC15913, p114RhoGEF
Ensembl gene	ENSG00000104880
Ensembl biotype	protein_coding
OMIM	616432
Entrez	23370

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000319670, ENST00000359920, ENST00000594665, ENST00000595600, ENST00000617428, ENST00000668164, ENST00000671891

RefSeq mRNA: 4 — MANE Select: NM_001367823 NM_001130955, NM_001367823, NM_001367824, NM_015318

CCDS: CCDS12177, CCDS45946, CCDS92502

Canonical transcript exons

ENST00000668164 — 29 exons

Exon	Start	End
ENSE00002633270	7362781	7362905
ENSE00002633562	7375720	7375870
ENSE00002635354	7379122	7379166
ENSE00002638025	7348937	7349241
ENSE00002646945	7380917	7380994
ENSE00002659597	7372812	7373071
ENSE00002677785	7378394	7378451
ENSE00002679904	7376643	7376757
ENSE00003014053	7383062	7383203
ENSE00003463000	7464560	7464690
ENSE00003556756	7440344	7440482
ENSE00003626608	7382792	7382894
ENSE00003736290	7470126	7472478
ENSE00003910371	7462152	7462334
ENSE00003911208	7458512	7458690
ENSE00003911246	7453467	7453715
ENSE00003911727	7467214	7467684
ENSE00003912326	7459903	7459994
ENSE00003912742	7467071	7467118
ENSE00003913160	7469904	7470029
ENSE00003913338	7451149	7451266
ENSE00003913998	7463818	7463955
ENSE00003914240	7468825	7469131
ENSE00003914412	7441653	7441765
ENSE00003914704	7441912	7442052
ENSE00003914990	7466918	7466974
ENSE00003915104	7447043	7447168
ENSE00003915415	7444204	7444454
ENSE00003916021	7456327	7456403

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4607 / max 391.5425, expressed in 1811 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173540	11.2120	1769
173532	5.0977	159
173541	3.3241	1393
173537	2.1612	190
173533	0.5066	99
173535	0.3022	87
173536	0.2293	108
173534	0.1944	62
173539	0.1796	75
173538	0.1604	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.23	gold quality
thymus	UBERON:0002370	96.85	gold quality
ileal mucosa	UBERON:0000331	96.48	gold quality
endothelial cell	CL:0000115	96.23	silver quality
cervix squamous epithelium	UBERON:0006922	95.40	silver quality
squamous epithelium	UBERON:0006914	93.58	gold quality
colonic mucosa	UBERON:0000317	93.50	gold quality
epithelium of esophagus	UBERON:0001976	93.26	gold quality
gingival epithelium	UBERON:0001949	93.25	gold quality
esophagus squamous epithelium	UBERON:0006920	93.25	gold quality
blood	UBERON:0000178	93.18	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.00	gold quality
renal medulla	UBERON:0000362	92.87	gold quality
amniotic fluid	UBERON:0000173	92.67	gold quality
gingiva	UBERON:0001828	92.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.27	gold quality
granulocyte	CL:0000094	92.17	gold quality
renal glomerulus	UBERON:0000074	92.15	gold quality
jejunal mucosa	UBERON:0000399	92.11	gold quality
parotid gland	UBERON:0001831	92.10	gold quality
middle temporal gyrus	UBERON:0002771	91.91	gold quality
metanephric glomerulus	UBERON:0004736	91.71	gold quality
periodontal ligament	UBERON:0008266	91.27	gold quality
epithelial cell of pancreas	CL:0000083	91.11	silver quality
spleen	UBERON:0002106	90.90	gold quality
inferior olivary complex	UBERON:0002127	90.78	gold quality
mucosa of transverse colon	UBERON:0004991	90.61	gold quality
decidua	UBERON:0002450	90.22	gold quality
trabecular bone tissue	UBERON:0002483	90.16	gold quality
primary visual cortex	UBERON:0002436	89.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	11.75
E-ANND-3	no	3.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting ARHGEF18, 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-4283	100.00	66.42	2097
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-1915-3P	99.58	66.79	1988

Literature-anchored findings (GeneRIF, showing 10)

• data showed that the novel guanine nucleotide exchange factor p114RhoGEF regulates the activity of RhoA and Rac1, and that Gbetagamma subunits of heterotrimeric G proteins are activators of p114RhoGEF under physiological conditions (PMID:14512443)
• p114-RhoGEF and Lfc are critically involved in Wnt-3a- and Dvl-induced RhoA activation and neurite retraction in N1E-115 cells. (PMID:20810787)
• Data indicate that p114RhoGEF is a component of a junction-associated Rho signalling module that drives spatially restricted activation of RhoA to regulate junction formation and epithelial morphogenesis. (PMID:21258369)
• In its regulation of the circumferential actomyosin tensile system, Lulu2 interacts with and activates p114RhoGEF at apical cell-cell junctions. (PMID:22006950)
• Stimulation of cortical myosin phosphorylation by p114RhoGEF drives cell migration and tumor cell invasion. (PMID:23185572)
• LKB1 and p114RhoGEF control RhoA activity in bronchial epithelial cells to promote apical junction assembly. (PMID:23648482)
• CRB3A recruits p114RhoGEF and its activator Ehm2 to the cell periphery using both functional motifs of its cytoplasmic tail and increases RhoA activation levels. (PMID:26217016)
• mutation of ARHGEF18 is a likely cause of inherited retinal dystrophy (PMID:28132693)
• We suggest that a portion of a 1361-residue isoform of ARHGEF18, which is unlike any other protein domain, has unique functions in control of polarity in activated eosinophils and other leukocytes (PMID:29601110)
• ARHGEF18 rs3745357 variant is associated with nonidiopathic pulmonary arterial hypertension susceptibility in Chinese population. (PMID:30405854)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	arhgef18a	ENSDARG00000011157
danio_rerio	arhgef18b	ENSDARG00000042308
mus_musculus	Arhgef18	ENSMUSG00000004568
rattus_norvegicus	Arhgef18	ENSRNOG00000028090
drosophila_melanogaster	cyst	FBGN0032796
caenorhabditis_elegans	prhg-1	WBGENE00022391

Paralogs (8): PLEKHG6 (ENSG00000008323), ARHGEF1 (ENSG00000076928), ARHGEF2 (ENSG00000116584), ARHGEF11 (ENSG00000132694), ARHGEF3 (ENSG00000163947), NET1 (ENSG00000173848), ARHGEF12 (ENSG00000196914), ARHGEF28 (ENSG00000214944)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor 18 — Q6ZSZ5 (reviewed: Q6ZSZ5)

Alternative names: 114 kDa Rho-specific guanine nucleotide exchange factor, Septin-associated RhoGEF

All UniProt accessions (7): Q6ZSZ5, A0A087WZG4, A0A3B3IPE9, A0A590UK10, A0A5F9ZHI8, A0A804CAZ4, M0QZS0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPases. Its activation induces formation of actin stress fibers. Also acts as a GEF for RAC1, inducing production of reactive oxygen species (ROS). Does not act as a GEF for CDC42. The G protein beta-gamma (Gbetagamma) subunits of heterotrimeric G proteins act as activators, explaining the integrated effects of LPA and other G-protein coupled receptor agonists on actin stress fiber formation, cell shape change and ROS production. Required for EPB41L4B-mediated regulation of the circumferential actomyosin belt in epithelial cells.

Subunit / interactions. Interacts with SEPT9; the interaction may inhibit GEF activity. Interacts with Gbetagamma subunits GNB1 and GNG2. Interacts with EPB41L4B. Interacts with PATJ (via C-terminus).

Subcellular location. Cytoplasm. Cytoskeleton. Cell membrane. Apical cell membrane.

Tissue specificity. Expressed in all tissues tested with highest expression in kidney and pancreas. Weakly or not expressed in liver, skeletal muscle and testis. Isoform 1: Expressed in eosinophils. Isoform 2: Expressed in eosinophils. Isoform 3: Expressed in eosinophils. Isoform 4: Not detected in eosinophils.

Disease relevance. Retinitis pigmentosa 78 (RP78) [MIM:617433] A form of retinitis pigmentosa, a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP78 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
Q6ZSZ5-4	1, LOCGEF-X3	yes
Q6ZSZ5-5	2, LOCGEF-X4
Q6ZSZ5-6	3, LOCGEF-X5
Q6ZSZ5-2	4, p114
Q6ZSZ5-1	5

RefSeq proteins (4): NP_001124427, NP_001354752, NP_001354753, NP_056133 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR037744	ARHGEF18_PH	Domain
IPR041020	PH_16	Domain
IPR053089	Rho_GEF18	Family

Pfam: PF00621, PF17838

UniProt features (40 total): compositionally biased region 10, region of interest 8, sequence variant 7, modified residue 4, splice variant 4, domain 2, sequence conflict 2, chain 1, coiled-coil region 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZSZ5-F1	62.10	0.27

Functional residue map

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

Post-translational modifications (4): 912, 921, 1289, 1291

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-2173791	TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-73887	Death Receptor Signaling
R-HSA-9006936	Signaling by TGFB family members
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 269 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_BUNDLE_ASSEMBLY, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_ACTOMYOSIN_STRUCTURE_ORGANIZATION, ACATTCC_MIR1_MIR206

GO Biological Process (6): small GTPase-mediated signal transduction (GO:0007264), regulation of cell shape (GO:0008360), actin cytoskeleton organization (GO:0030036), regulation of Rho protein signal transduction (GO:0035023), negative regulation of stress fiber assembly (GO:0051497), protein localization to cell-cell junction (GO:0150105)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), cell junction (GO:0030054), apical part of cell (GO:0045177), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Signal Transduction	4
RHO GTPase cycle	2
Cell death signalling via NRAGE, NRIF and NADE	1
Signaling by TGF-beta Receptor Complex	1
GPCR downstream signalling	1
Signaling by TGFB family members	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Signaling by GPCR	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
intracellular signaling cassette	1
regulation of cell morphogenesis	1
regulation of biological quality	1
cytoskeleton organization	1
actin filament-based process	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
negative regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
protein localization to cell junction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
transition metal ion binding	1
binding	1
cation binding	1
cytoplasm	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARHGEF18	CGN	Q9P2M7	923
ARHGEF18	CGNL1	Q0VF96	872
ARHGEF18	ROCK2	O75116	865
ARHGEF18	TJP1	Q07157	735
ARHGEF18	RHOA	P06749	727
ARHGEF18	EPB41L4B	Q9H329	607
ARHGEF18	STK11	Q15831	515
ARHGEF18	ECT2	Q9H8V3	438
ARHGEF18	CDC42BPB	Q9Y5S2	436
ARHGEF18	MCF2	P10911	436
ARHGEF18	DLG4	P78352	403
ARHGEF18	PALS1	Q8N3R9	400
ARHGEF18	ARHGAP17	Q68EM7	386
ARHGEF18	ABR	Q12979	384
ARHGEF18	ARHGAP35	Q9NRY4	384

IntAct

16 interactions, top by confidence:

A	B	Type	Score
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
LTBR	ZNF724	psi-mi:“MI:0914”(association)	0.530
AKIRIN2	RGPD8	psi-mi:“MI:0914”(association)	0.530
ZMYND11	ARHGEF18	psi-mi:“MI:0407”(direct interaction)	0.440
AKAP13	ARHGEF18	psi-mi:“MI:0915”(physical association)	0.400
ARHGEF18	AKAP13	psi-mi:“MI:0915”(physical association)	0.400
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
ARHGEF28	ARHGEF9	psi-mi:“MI:0914”(association)	0.350
RHOA	TAX1BP3	psi-mi:“MI:0914”(association)	0.350
PLOD1	PLOD2	psi-mi:“MI:0914”(association)	0.350
DCP2	VSIG8	psi-mi:“MI:0914”(association)	0.350
EPB41L5	SAP18	psi-mi:“MI:0914”(association)	0.350
CNTRL	CCDC85C	psi-mi:“MI:2364”(proximity)	0.270
	ARHGEF18	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (48): ARHGEF18 (Affinity Capture-MS), ARHGEF18 (Proximity Label-MS), ARHGEF18 (Affinity Capture-MS), ARHGEF18 (Affinity Capture-RNA), GNB1 (Affinity Capture-Western), ARHGEF18 (Affinity Capture-RNA), ARHGEF18 (Reconstituted Complex), ARHGEF18 (Affinity Capture-MS), ARHGEF18 (Affinity Capture-MS), ARHGEF18 (Affinity Capture-Western), ARHGEF18 (Reconstituted Complex), GART (Affinity Capture-MS), CFL1 (Affinity Capture-MS), SLIRP (Affinity Capture-MS), ARHGEF18 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A0A8M9QN10, A1L1G9, A2ARK0, A3KN19, A4QP72, A6QQ70, D4A929, O43147, O60307, O75064, O75427, P46062, P58660, P97433, Q08AE8, Q2KI85, Q2TAL5, Q3U1V8, Q3U1Y4, Q3U214, Q3UHC7, Q5PQS0, Q5SWY7, Q5SXA9, Q5U3H9, Q5U464, Q5VWQ8, Q5XGY0, Q66K74, Q66L42, Q6P1I6, Q6P730, Q6P9R4, Q6PF42, Q6ZSZ5, Q8C0J6, Q8C2B3, Q8C2K5, Q8CI12

Diamond homologs: B2DCZ9, E9Q394, F1M3G7, P0C6P5, P97433, Q12802, Q5FVC2, Q60875, Q6P9R4, Q6ZSZ5, Q865S3, Q8N1W1, Q92974, Q9NZN5, Q61210, Q92888, Q9Z1I6, O15085, Q5ZLX4, Q8R4H2, Q9ES67, O94827, Q5R6F2, Q66T02, Q6RFZ7, Q9N0A8, Q9NR81, A0A8P0N4K0, A4D2P6, A5PKA5, A8MUH7, D3YZU1, Q0QWG9, Q14160, Q15811, Q3T0C9, Q3T0X8, Q3UHD6, Q4ACU6, Q4H4B6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SEPTIN9	down-regulates	ARHGEF18	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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
Signaling by Rho GTPases	5	10.1×	3e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	5	9.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1144 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	7
Uncertain significance	543
Likely benign	460
Benign	58

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1068967	NM_001367823.1(ARHGEF18):c.968-300_968-290del	Pathogenic
1076113	NM_001367823.1(ARHGEF18):c.3145C>T (p.Gln1049Ter)	Pathogenic
1076913	NM_001367823.1(ARHGEF18):c.968-377del	Pathogenic
1452236	NM_001367823.1(ARHGEF18):c.3340C>T (p.Gln1114Ter)	Pathogenic
1454778	NM_001367823.1(ARHGEF18):c.3726dup (p.Thr1243fs)	Pathogenic
1997749	NM_001367823.1(ARHGEF18):c.2827C>T (p.Arg943Ter)	Pathogenic
2001510	NM_001367823.1(ARHGEF18):c.1582C>T (p.Gln528Ter)	Pathogenic
2020973	NM_001367823.1(ARHGEF18):c.1150A>T (p.Lys384Ter)	Pathogenic
2023005	NM_001367823.1(ARHGEF18):c.3837del (p.Asp1280fs)	Pathogenic
2087890	NM_001367823.1(ARHGEF18):c.1885C>T (p.Gln629Ter)	Pathogenic
2132409	NM_001367823.1(ARHGEF18):c.2868del (p.Ser956fs)	Pathogenic
2873837	NM_001367823.1(ARHGEF18):c.1054_1057del (p.Lys352fs)	Pathogenic
3018532	NM_001367823.1(ARHGEF18):c.968-298A>T	Pathogenic
3248423	NC_000019.9:g.(?7504827)(7712696_?)del	Pathogenic
417755	NM_001367823.1(ARHGEF18):c.2560C>T (p.Arg854Ter)	Pathogenic
417756	NM_001367823.1(ARHGEF18):c.3302_3325del (p.Arg1101_Glu1108del)	Pathogenic
417757	NM_001367823.1(ARHGEF18):c.3196G>T (p.Glu1066Ter)	Pathogenic
4708364	NM_001367823.1(ARHGEF18):c.968-301_968-258del	Pathogenic
4724151	NM_001367823.1(ARHGEF18):c.2957C>A (p.Ser986Ter)	Pathogenic
941795	NM_001367823.1(ARHGEF18):c.2661_2670del (p.Cys887fs)	Pathogenic
970053	NM_001367823.1(ARHGEF18):c.1588dup (p.Ile530fs)	Pathogenic
1031128	NM_001367823.1(ARHGEF18):c.2905-1G>T	Likely pathogenic
3393420	NM_001367823.1(ARHGEF18):c.275+1G>T	Likely pathogenic
3892982	NM_001367823.1(ARHGEF18):c.294dup (p.Ala99fs)	Likely pathogenic
417754	NM_001367823.1(ARHGEF18):c.1372A>G (p.Thr458Ala)	Likely pathogenic
4715643	NM_001367823.1(ARHGEF18):c.2773+1G>A	Likely pathogenic
4765100	NM_001367823.1(ARHGEF18):c.3481-1G>C	Likely pathogenic
4849288	NM_001367823.1(ARHGEF18):c.112del (p.Ala40fs)	Likely pathogenic

SpliceAI

4995 predictions. Top by Δscore:

Variant	Effect	Δscore
19:7372975:G:GT	donor_gain	1.0000
19:7378450:GT:G	donor_gain	1.0000
19:7378452:G:GG	donor_gain	1.0000
19:7380992:GGA:G	donor_gain	1.0000
19:7380993:GA:G	donor_gain	1.0000
19:7380993:GAG:G	donor_gain	1.0000
19:7382790:A:AG	acceptor_gain	1.0000
19:7382790:AG:A	acceptor_gain	1.0000
19:7382791:G:A	acceptor_loss	1.0000
19:7382791:G:GT	acceptor_gain	1.0000
19:7382791:GG:G	acceptor_gain	1.0000
19:7382791:GGA:G	acceptor_gain	1.0000
19:7382791:GGAGC:G	acceptor_gain	1.0000
19:7382891:GAAG:G	donor_gain	1.0000
19:7382892:AAGGT:A	donor_loss	1.0000
19:7382894:GGTAA:G	donor_loss	1.0000
19:7382895:G:GC	donor_loss	1.0000
19:7382896:T:G	donor_loss	1.0000
19:7383057:T:G	acceptor_gain	1.0000
19:7383058:CCA:C	acceptor_loss	1.0000
19:7383059:CA:C	acceptor_loss	1.0000
19:7383060:A:AG	acceptor_gain	1.0000
19:7383060:AG:A	acceptor_gain	1.0000
19:7383060:AGG:A	acceptor_gain	1.0000
19:7383061:G:GG	acceptor_gain	1.0000
19:7383061:GG:G	acceptor_gain	1.0000
19:7383061:GGG:G	acceptor_gain	1.0000
19:7383061:GGGGA:G	acceptor_gain	1.0000
19:7395246:AGG:A	donor_loss	1.0000
19:7395248:GT:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000006809 (19:7350316 G>A), RS1000027477 (19:7423301 A>G), RS1000072425 (19:7412227 G>A), RS1000074795 (19:7361994 A>C,G), RS1000106852 (19:7478766 G>A), RS1000108022 (19:7430985 AGC>A), RS1000109540 (19:7427686 C>T), RS1000110186 (19:7355812 G>A), RS1000118204 (19:7479027 C>T), RS1000137087 (19:7413301 T>C), RS1000144401 (19:7356127 CAT>C), RS1000167724 (19:7383338 T>A,C,G), RS1000219139 (19:7383446 A>G), RS1000222618 (19:7420474 A>G), RS1000257772 (19:7425439 T>C)

Disease associations

OMIM: gene MIM:616432 | disease phenotypes: MIM:617433, MIM:252650

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 78	Strong	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
inherited retinal dystrophy	Moderate	AR

Mondo (5): inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa 78 (MONDO:0044314), optic atrophy (MONDO:0003608), mucolipidosis type IV (MONDO:0009653), retinitis pigmentosa (MONDO:0019200)

Orphanet (2): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Mucolipidosis type IV (Orphanet:578)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001123	Visual field defect
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007843	Attenuation of retinal blood vessels
HP:0007994	Peripheral visual field loss
HP:0008046	Abnormal retinal vascular morphology
HP:0011462	Young adult onset
HP:0011505	Cystoid macular edema
HP:0012426	Optic disc drusen

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Benzo(a)pyrene	decreases methylation, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	increases methylation	2
FR900359	affects phosphorylation	1
aflatoxin B2	decreases methylation	1
coumarin	increases phosphorylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
beta-methylcholine	affects expression	1
arsenic disulfide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Arsenic	affects methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Calcitriol	affects cotreatment, increases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa