RAB18

Summary

RAB18 (RAB18, member RAS oncogene family, HGNC:14244) is a protein-coding gene on chromosome 10p12.1, encoding Ras-related protein Rab-18 (Q9NP72). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. It is a selective cancer dependency (DepMap: 13.3% of cell lines).

The protein encoded by this gene is a member of a family of Ras-related small GTPases that regulate membrane trafficking in organelles and transport vesicles. Knockdown studies is zebrafish suggest that this protein may have a role in eye and brain development. Mutations in this gene are associated with Warburg micro syndrome type 3. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 22931 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Warburg micro syndrome 3 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 199 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 78
• Cancer dependency (DepMap): dependent in 13.3% of screened cell lines
• MANE Select transcript: NM_021252

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14244
Approved symbol	RAB18
Name	RAB18, member RAS oncogene family
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000099246
Ensembl biotype	protein_coding
OMIM	602207
Entrez	22931

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 15 protein_coding, 13 nonsense_mediated_decay, 10 protein_coding_CDS_not_defined, 8 retained_intron

ENST00000356940, ENST00000375802, ENST00000423465, ENST00000465772, ENST00000484281, ENST00000490236, ENST00000535776, ENST00000611151, ENST00000621805, ENST00000682082, ENST00000682138, ENST00000682173, ENST00000682181, ENST00000682347, ENST00000682368, ENST00000682389, ENST00000682518, ENST00000682668, ENST00000682681, ENST00000682777, ENST00000682821, ENST00000682852, ENST00000682963, ENST00000683030, ENST00000683042, ENST00000683088, ENST00000683385, ENST00000683419, ENST00000683446, ENST00000683538, ENST00000683574, ENST00000683610, ENST00000683755, ENST00000683797, ENST00000683816, ENST00000683844, ENST00000683866, ENST00000683915, ENST00000683924, ENST00000684134, ENST00000684191, ENST00000684393, ENST00000684457, ENST00000684501, ENST00000684744, ENST00000964579

RefSeq mRNA: 4 — MANE Select: NM_021252 NM_001256410, NM_001256411, NM_001256412, NM_021252

CCDS: CCDS58073, CCDS7155, CCDS73081, CCDS91231

Canonical transcript exons

ENST00000356940 — 7 exons

Exon	Start	End
ENSE00001415399	27537876	27542239
ENSE00001907702	27504304	27504437
ENSE00003393549	27533928	27533994
ENSE00003507846	27526828	27526889
ENSE00003612794	27509875	27509930
ENSE00003654355	27532507	27532579
ENSE00003671212	27533735	27533853

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.9202 / max 997.1908, expressed in 1815 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104451	66.0420	1812
104452	6.8783	1704

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.92	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.83	gold quality
upper arm skin	UBERON:0004263	98.71	gold quality
left ventricle myocardium	UBERON:0006566	98.41	gold quality
decidua	UBERON:0002450	98.31	gold quality
calcaneal tendon	UBERON:0003701	98.22	gold quality
tibialis anterior	UBERON:0001385	98.09	gold quality
pigmented layer of retina	UBERON:0001782	98.02	gold quality
myocardium	UBERON:0002349	98.00	gold quality
islet of Langerhans	UBERON:0000006	97.88	gold quality
ileal mucosa	UBERON:0000331	97.64	gold quality
corpus epididymis	UBERON:0004359	97.54	gold quality
cartilage tissue	UBERON:0002418	97.43	gold quality
cauda epididymis	UBERON:0004360	97.43	gold quality
deltoid	UBERON:0001476	97.42	gold quality
esophagus squamous epithelium	UBERON:0006920	97.41	gold quality
heart right ventricle	UBERON:0002080	97.30	gold quality
stromal cell of endometrium	CL:0002255	97.16	gold quality
epithelial cell of pancreas	CL:0000083	97.07	gold quality
caput epididymis	UBERON:0004358	97.07	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.04	gold quality
jejunal mucosa	UBERON:0000399	97.03	gold quality
ganglionic eminence	UBERON:0004023	96.98	gold quality
upper leg skin	UBERON:0004262	96.93	gold quality
cortical plate	UBERON:0005343	96.92	gold quality
oral cavity	UBERON:0000167	96.84	gold quality
pons	UBERON:0000988	96.82	gold quality
kidney epithelium	UBERON:0004819	96.80	gold quality
substantia nigra pars compacta	UBERON:0001965	96.77	gold quality
ventricular zone	UBERON:0003053	96.73	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-75367	no	1014.68
E-CURD-112	no	3.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CAMTA1, CREB1, RBPJ, SMARCC1

miRNA regulators (miRDB)

172 targeting RAB18, 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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 31)

• Rab18 regulates lipid droplet-associated membrane formation (PMID:15914536)
• analysis of a novel splice variant of human Rab18 gene (PMID:16147880)
• Rab18 is recruited to lipid droplets during lipolysis (PMID:16207721)
• The results suggested that the putative hydrophobic cleft is critical for the unique characteristics of TIP47. (PMID:16808905)
• Rab18 is reduced in pituitary tumors causing acromegaly and its overexpression reverts growth hormone hypersecretion. (PMID:18349058)
• Rab18 and Rab43 have key roles in ER-Golgi trafficking. (PMID:18664496)
• performed autozygosity mapping in five consanguineous families with Warburg micro syndrome without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18 (PMID:21473985)
• Micro syndrome has been associated with causative mutations in three disease genes: RAB3GAP1, RAB3GAP2 and RAB18. Martsolf syndrome has been associated with a mutation in RAB3GAP2. [Review] (PMID:23176487)
• One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases (PMID:23420520)
• Hepatitis B virus X protein enhances proliferation of hepatoma cells through Rab18. (PMID:23471881)
• Rab18 interacts with the HCV nonstructural protein NS5A. (PMID:23935497)
• High RAB18 expression is associated with glioma. (PMID:24477653)
• Rab18-mediated membrane trafficking of FASN and NS3 facilitates dengue virus replication. (PMID:24696471)
• Rab18 and a Rab18 GEF complex of Rab3GAP1 and Rab3GAP2 have roles in the endoplasmic reticulum structure (PMID:24891604)
• findings suggest that RAB18 rs3765133 polymorphism affects the development of specific brain regions, particularly the cerebellum, in healthy people. (PMID:24996981)
• These results suggest that Rab18 has an important role in viral assembly through the trafficking of the hepatitis C virus core protein to lipid droplets. (PMID:24997429)
• Warburg Micro syndrome is caused by RAB18 deficiency. (PMID:26063829)
• RAB18 is the direct target of miR-455-5p in gastric cancer. (PMID:27451075)
• The authors found that the previously documented interaction between TRAPPII and COPI was also required for the recruitment of Rab18 to the lipid droplet. (PMID:28003315)
• RAB18 modulates macroautophagy and proteostasis, and is dependent on activity of RAB3GAP1 and RAB3GAP2. (PMID:28342870)
• Rab18 is not a general, necessary component of the protein machinery involved in lipid droplet biogenesis or turnover. (PMID:29949452)
• Studies suggest that rab GTP-binding protein Rab18 (Rab18) functions related to organelle tethering and to autophagy [Review]. (PMID:30830238)
• The study elucidates a role for RAB18 in autophagy and regulation of proteostasis in human stellate cells. (PMID:31563421)
• Rab18 plays a role upstream of the cytosolic lipolytic enzyme adipose triglyceride lipase (ATGL) and that recruitment of ATGL by Rab18 is mediated by elements of the Arf/GBF1 machinery. We find that Arf4-GFP is accumulated on the subset of lipid droplets associated with Rab18. (PMID:31610914)
• The Warburg Micro Syndrome-associated Rab3GAP-Rab18 module promotes autolysosome maturation through the Vps34 Complex I. (PMID:32248620)
• Rab18 regulates focal adhesion dynamics by interacting with kinectin-1 at the endoplasmic reticulum. (PMID:32525992)
• Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights. (PMID:32740904)
• Rab18 interacted with V-set and immunoglobulin domain-containing 4 (VSIG4) to involve in the apoptosis of glioma and the sensitivity to temozolomide. (PMID:33904378)
• Rab18 Drift in Lipid Droplet and Endoplasmic Reticulum Interactions of Adipocytes under Obesogenic Conditions. (PMID:38139006)
• Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders. (PMID:38523235)
• 2'3’-cGAMP interactome identifies 2'3’-cGAMP/Rab18/FosB signaling in cell migration control independent of innate immunity. (PMID:39413198)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab18b	ENSDARG00000098344
mus_musculus	Rab18	ENSMUSG00000073639
rattus_norvegicus	AABR07068154.1	ENSRNOG00000027719

Paralogs (68): RAB27B (ENSG00000041353), RAB27A (ENSG00000069974), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB40AL (ENSG00000102128), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), RAB35 (ENSG00000111737), RAB23 (ENSG00000112210), DNAJC27 (ENSG00000115137), RAB29 (ENSG00000117280), RAB32 (ENSG00000118508), RAB14 (ENSG00000119396), RAB9B (ENSG00000123570), RAB9A (ENSG00000123595), RAB38 (ENSG00000123892), RAB22A (ENSG00000124209), RAB17 (ENSG00000124839), RAB2B (ENSG00000129472), RAB25 (ENSG00000132698), RAB33A (ENSG00000134594), RAB30 (ENSG00000137502), RAB1A (ENSG00000138069), RAB20 (ENSG00000139832), RAB15 (ENSG00000139998), RAB40B (ENSG00000141542), RAB13 (ENSG00000143545), RABL2A (ENSG00000144134), RAB5A (ENSG00000144566), RAB19 (ENSG00000146955), RAB41 (ENSG00000147127)

Protein

Protein identifiers

Ras-related protein Rab-18 — Q9NP72 (reviewed: Q9NP72)

All UniProt accessions (22): A0A087X163, A0A804HIB9, A0A804HIM2, A0A804HIY1, A0A804HJ83, A0A804HJJ8, A0A804HK95, A0A804HKH8, A0A804HKK5, A0A804HKK8, A0A804HKV1, A0A804HL33, A0A804HL37, A0A804HL88, A0A804HLG5, A0A804HLH7, A0A804HLK4, A0A8C8NLQ3, B7Z4P9, Q9NP72, H0Y6T8, Q5W0J0

UniProt curated annotations — full annotation on UniProt →

Function. The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. RAB18 is required for the localization of ZFYVE1 to lipid droplets and for its function in mediating the formation of endoplasmic reticulum-lipid droplets (ER-LD) contacts. Also required for maintaining endoplasmic reticulum structure. Plays a role in apical endocytosis/recycling. Plays a key role in eye and brain development and neurodegeneration.

Subunit / interactions. Interacts (in GTP-bound form) with ZFYVE1. Interacts with ZW10 and this interaction is enhanced in the presence of ZFYVE1. Interacts with BSCL2. (Microbial infection) Interacts with Hepatitis C virus (HCV) non-structural protein 5A; this interaction may promote the association of NS5A and other viral replicase components with lipid droplets.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. cis-Golgi network membrane. Lipid droplet. Apical cell membrane.

Tissue specificity. Ubiquitous.

Disease relevance. Warburg micro syndrome 3 (WARBM3) [MIM:614222] A rare syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe intellectual disability, spastic diplegia, and hypogonadism. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulated by guanine nucleotide exchange factor (GEF) RAB3GAP1-RAB3GAP2 complex at the cis-Golgi membrane which promotes the exchange of bound GDP for free GTP. Regulated by GTPase activating protein (GAP) TBC1D20 at the ER membrane which increases the GTP hydrolysis activity. Inhibited by GDP dissociation inhibitors (GDIs) which prevent Rab-GDP dissociation.

Domain organisation. Switch 1, switch 2 and the interswitch regions are characteristic of Rab GTPases and mediate the interactions with Rab downstream effectors. The switch regions undergo conformational changes upon nucleotide binding which drive interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

Miscellaneous. Highly expressed in testis.

Similarity. Belongs to the small GTPase superfamily. Rab family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NP72-1	1	yes
Q9NP72-2	2
Q9NP72-3	3

RefSeq proteins (4): NP_001243339, NP_001243340, NP_001243341, NP_067075* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR025662	Sigma_54_int_dom_ATP-bd_1	Binding_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR050227	Rab	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (52 total): binding site 14, helix 8, strand 7, sequence variant 5, mutagenesis site 5, modified residue 3, short sequence motif 2, lipid moiety-binding region 2, splice variant 2, chain 1, propeptide 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1X3S	X-RAY DIFFRACTION	1.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP72-F1	86.10	0.66

Functional residue map

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

Ligand- & substrate-binding residues (14): 34; 35; 40; 40; 66; 123; 125; 152; 17; 20; 21; 22 …

Post-translational modifications (5): 1, 144, 203, 199, 203

Mutagenesis-validated functional residues (5):

Position	Phenotype
22	loss of localization to lipid droplets and interaction with zfyve1.
67	no loss of localization to lipid droplets and interaction with zfyve1.
133	impaired gdp/gtp exchange by the rab3gap1-rab3gap2 complex.
141	impaired gdp/gtp exchange by the rab3gap1-rab3gap2 complex.
164	impaired gdp/gtp exchange by the rab3gap1-rab3gap2 complex.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 391 (showing top): TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, REACTOME_MEMBRANE_TRAFFICKING, WANG_LMO4_TARGETS_DN, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_HEAD_DEVELOPMENT, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, JIANG_AGING_HYPOTHALAMUS_DN

GO Biological Process (7): eye development (GO:0001654), intracellular protein transport (GO:0006886), small GTPase-mediated signal transduction (GO:0007264), brain development (GO:0007420), lipid droplet organization (GO:0034389), endoplasmic reticulum tubular network organization (GO:0071786), protein transport (GO:0015031)

GO Molecular Function (7): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (12): endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), lipid droplet (GO:0005811), cytosol (GO:0005829), plasma membrane (GO:0005886), endomembrane system (GO:0012505), apical plasma membrane (GO:0016324), secretory granule membrane (GO:0030667), cis-Golgi network membrane (GO:0033106), endoplasmic reticulum tubular network (GO:0071782), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Golgi-to-ER retrograde transport	1
Post-translational protein modification	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
intracellular protein localization	2
guanyl ribonucleotide binding	2
endoplasmic reticulum subcompartment	2
endomembrane system	2
intracellular membrane-bounded organelle	2
bounding membrane of organelle	2
sensory organ development	1
visual system development	1
protein transport	1
intracellular transport	1
intracellular signaling cassette	1
central nervous system development	1
animal organ development	1
head development	1
organelle organization	1
endoplasmic reticulum organization	1
transport	1
establishment of protein localization	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1
apical part of cell	1
plasma membrane region	1
secretory granule	1
cytoplasmic vesicle membrane	1

Protein interactions and networks

STRING

1804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB18	RINT1	Q6NUQ1	931
RAB18	ZW10	O43264	876
RAB18	RAB3GAP2	Q9H2M9	868
RAB18	RAB3GAP1	Q15042	863
RAB18	TBC1D20	Q96BZ9	791
RAB18	STX18	Q9P2W9	775
RAB18	PLIN3	O60664	740
RAB18	PLIN2	Q99541	713
RAB18	BSCL2	Q96G97	703
RAB18	PLIN4	Q96Q06	610
RAB18	ZFYVE1	Q9HBF4	608
RAB18	BNIP1	Q12981	582
RAB18	SNX14	Q9Y5W7	549
RAB18	FASN	P49327	533
RAB18	TBC1D5	Q92609	519
RAB18	RAB19	A4D1S5	519

IntAct

129 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
GDI1	RAB4A	psi-mi:“MI:0914”(association)	0.820
PPP2R1B	STRN	psi-mi:“MI:0914”(association)	0.730
	PI4KA	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SFXN5	CTSA	psi-mi:“MI:0914”(association)	0.640
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
RAB18		psi-mi:“MI:0403”(colocalization)	0.570
RAB18		psi-mi:“MI:0915”(physical association)	0.570
	RAB18	psi-mi:“MI:0403”(colocalization)	0.570
RAB18	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.560
ELOVL4	RAB18	psi-mi:“MI:0915”(physical association)	0.560
AQP6	RAB18	psi-mi:“MI:0915”(physical association)	0.560
rep	AGPS	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
SLC15A1	METTL15	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
CD244	MTX2	psi-mi:“MI:0914”(association)	0.530

BioGRID (189): RAB18 (Two-hybrid), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Affinity Capture-MS), RAB18 (Proximity Label-MS), RAB18 (Proximity Label-MS), RAB18 (Two-hybrid)

ESM2 similar proteins: A4D1S5, O13876, O80501, P05714, P10948, P10949, P20337, P20338, P34213, P35289, P35293, P35294, P51152, P51159, P56371, P62823, P90726, Q05976, Q0IIG8, Q15771, Q17QB7, Q18969, Q1HE58, Q28IZ3, Q2TBH7, Q32NQ0, Q3ZC27, Q53B90, Q54E92, Q55FK2, Q5EB77, Q5KTJ7, Q5M7U5, Q5R5H5, Q63941, Q68EK7, Q6DHC1, Q6PHI9, Q8CG50, Q923S9

Diamond homologs: E9Q9D5, G4MYS1, I1RMF2, O01803, O04486, O35509, O42819, O49513, O76173, O94655, P07560, P10536, P11620, P22125, P22129, P24408, P28185, P28187, P28188, P31584, P32939, P33519, P33723, P34139, P34140, P35293, P36412, P38545, P38555, P40392, P40393, P41924, P46638, P51151, P62490, P62491, P62492, P62493, P62494, P62820

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	99
Likely benign	33
Benign	36

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
100768	NM_021252.5(RAB18):c.284C>G (p.Thr95Arg)	Pathogenic
2875520	NM_021252.5(RAB18):c.276_277del (p.Asp94fs)	Pathogenic
30247	NM_021252.5(RAB18):c.71T>A (p.Leu24Gln)	Pathogenic
30248	NG_032035.1:g.(5265_10701)_(10758_27654)del	Pathogenic
30249	NM_021252.5(RAB18):c.274AGA[1] (p.Arg93del)	Pathogenic
30250	NM_021252.5(RAB18):c.619T>C (p.Ter207Gln)	Pathogenic
3777096	NM_021252.5(RAB18):c.460del (p.Thr154fs)	Likely pathogenic
3777097	NM_021252.5(RAB18):c.272C>T (p.Thr91Ile)	Likely pathogenic
4077456	NM_021252.5(RAB18):c.125-23A>G	Likely pathogenic
915279	NM_021252.5(RAB18):c.549del (p.Gly184fs)	Likely pathogenic

SpliceAI

1255 predictions. Top by Δscore:

Variant	Effect	Δscore
10:27504434:CCAG:C	donor_loss	1.0000
10:27504436:AGG:A	donor_loss	1.0000
10:27504438:G:A	donor_loss	1.0000
10:27509873:A:AG	acceptor_gain	1.0000
10:27509873:AGCCT:A	acceptor_gain	1.0000
10:27509874:G:GA	acceptor_gain	1.0000
10:27509874:GC:G	acceptor_gain	1.0000
10:27509874:GCC:G	acceptor_gain	1.0000
10:27509874:GCCT:G	acceptor_gain	1.0000
10:27509874:GCCTG:G	acceptor_gain	1.0000
10:27509928:TAGG:T	donor_loss	1.0000
10:27509929:AGG:A	donor_loss	1.0000
10:27509930:GGTAA:G	donor_loss	1.0000
10:27509931:G:GC	donor_loss	1.0000
10:27509932:T:A	donor_loss	1.0000
10:27530147:G:GT	donor_gain	1.0000
10:27533733:A:AG	acceptor_gain	1.0000
10:27533734:G:GG	acceptor_gain	1.0000
10:27533734:GT:G	acceptor_gain	1.0000
10:27533734:GTTT:G	acceptor_gain	1.0000
10:27533922:TTTTA:T	acceptor_loss	1.0000
10:27533923:TTTA:T	acceptor_loss	1.0000
10:27533924:TTA:T	acceptor_loss	1.0000
10:27533925:TA:T	acceptor_loss	1.0000
10:27533926:AGGAA:A	acceptor_loss	1.0000
10:27533927:G:GC	acceptor_loss	1.0000
10:27533992:TAGGT:T	donor_loss	1.0000
10:27533994:GG:G	donor_loss	1.0000
10:27533995:G:GA	donor_loss	1.0000
10:27537960:A:T	donor_gain	1.0000

AlphaMissense

1351 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:27504413:G:T	G15V	1.000
10:27504427:G:C	G20R	1.000
10:27504431:A:T	K21M	1.000
10:27509903:T:C	F33L	1.000
10:27509905:T:A	F33L	1.000
10:27509905:T:G	F33L	1.000
10:27509930:G:C	G42R	1.000
10:27526836:T:C	F45L	1.000
10:27526838:T:A	F45L	1.000
10:27526838:T:G	F45L	1.000
10:27526885:T:A	I61K	1.000
10:27526887:T:A	W62R	1.000
10:27526887:T:C	W62R	1.000
10:27532507:G:C	D63H	1.000
10:27532508:A:C	D63A	1.000
10:27532508:A:T	D63V	1.000
10:27532514:C:A	A65D	1.000
10:27532516:G:C	G66R	1.000
10:27532516:G:T	G66C	1.000
10:27532517:G:A	G66D	1.000
10:27532528:T:C	F70L	1.000
10:27532529:T:C	F70S	1.000
10:27532530:T:A	F70L	1.000
10:27532530:T:G	F70L	1.000
10:27533843:A:T	K123I	1.000
10:27504404:T:A	L12H	0.999
10:27504404:T:C	L12P	0.999
10:27504412:G:C	G15R	0.999
10:27504412:G:T	G15C	0.999
10:27504413:G:A	G15D	0.999

dbSNP variants (sampled 300 via entrez): RS1000142586 (10:27513063 C>T), RS1000293606 (10:27506380 G>T), RS1000300515 (10:27506415 G>C), RS1000347958 (10:27519192 G>T), RS1000398866 (10:27506718 A>G), RS1000405991 (10:27512684 G>A), RS1000472024 (10:27542376 AGT>A), RS1000700694 (10:27517745 G>C), RS1000847113 (10:27530870 A>G), RS1000909135 (10:27537580 C>T), RS1000917388 (10:27524242 T>C), RS1000933439 (10:27508012 C>G), RS1000962940 (10:27511797 C>A,G,T), RS1001096551 (10:27531553 A>G), RS1001176076 (10:27506299 G>A)

Disease associations

OMIM: gene MIM:602207 | disease phenotypes: MIM:614222

GenCC curated gene-disease

Disease	Classification	Inheritance
Warburg micro syndrome 3	Definitive	Autosomal recessive
Warburg micro syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Warburg micro syndrome	Moderate	AR

Mondo (2): Warburg micro syndrome 3 (MONDO:0013638), Warburg micro syndrome (MONDO:0016649)

Orphanet (1): Micro syndrome (Orphanet:2510)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000126	Hydronephrosis
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000294	Low anterior hairline
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000480	Retinal coloboma
HP:0000482	Microcornea
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis
HP:0000594	Shallow anterior chamber
HP:0000616	Miosis
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000823	Delayed puberty

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002875_97	Diisocyanate-induced asthma	2.000000e-06
GCST003991_3	Childhood ear infection	5.000000e-16
GCST005013_11	Childhood ear infection	5.000000e-16
GCST006288_470	Heel bone mineral density	4.000000e-07
GCST006288_488	Heel bone mineral density	1.000000e-08
GCST006288_628	Heel bone mineral density	4.000000e-15
GCST006979_565	Heel bone mineral density	1.000000e-41
GCST008156_58	Hip circumference adjusted for BMI	4.000000e-06
GCST008839_31	Height	2.000000e-12
GCST010002_284	Refractive error	1.000000e-08
GCST010566_6	Benign childhood epilepsy with centro-temporal spikes	2.000000e-06
GCST90020024_218	A body shape index	1.000000e-08
GCST90020029_132	Waist circumference adjusted for body mass index	7.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0009270	heel bone mineral density
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment	5
bisphenol A	decreases expression, increases expression, affects cotreatment	3
deoxynivalenol	increases expression	2
sodium arsenite	increases expression, decreases expression, increases abundance	2
entinostat	decreases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression, affects expression	2
Tobacco Smoke Pollution	increases expression	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	increases expression	1
trichostatin A	increases expression	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	affects binding	1
ochratoxin B	affects binding	1
di-n-butylphosphoric acid	affects expression	1
10-decarbamoylmitomycin C	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
ICG 001	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford