RAB35

Summary

RAB35 (RAB35, member RAS oncogene family, HGNC:9774) is a protein-coding gene on chromosome 12q24.23, encoding Ras-related protein Rab-35 (Q15286). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

Enables GTPase activity and anion binding activity. Involved in several processes, including endosomal transport; plasma membrane to endosome transport; and protein localization to endosome. Located in several cellular components, including clathrin-coated endocytic vesicle; clathrin-coated pit; and intercellular bridge.

Source: NCBI Gene 11021 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 15 total
• Druggable target: yes
• MANE Select transcript: NM_006861

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9774
Approved symbol	RAB35
Name	RAB35, member RAS oncogene family
Location	12q24.23
Locus type	gene with protein product
Status	Approved
Aliases	H-ray
Ensembl gene	ENSG00000111737
Ensembl biotype	protein_coding
OMIM	604199
Entrez	11021

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000229340, ENST00000534951, ENST00000538903, ENST00000540803, ENST00000543364, ENST00000544304, ENST00000876258, ENST00000921614, ENST00000921615, ENST00000960166, ENST00000960167

RefSeq mRNA: 2 — MANE Select: NM_006861 NM_001167606, NM_006861

CCDS: CCDS41846, CCDS53836

Canonical transcript exons

ENST00000229340 — 6 exons

Exon	Start	End
ENSE00001633286	120095099	120097373
ENSE00002235546	120116599	120116753
ENSE00003473622	120103826	120103949
ENSE00003482648	120098811	120098935
ENSE00003524984	120099030	120099154
ENSE00003656129	120108417	120108467

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 93.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.9469 / max 199.4382, expressed in 1818 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133591	22.0949	1817
133592	1.8283	1237
133590	1.0237	704

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	93.59	gold quality
granulocyte	CL:0000094	93.45	gold quality
stromal cell of endometrium	CL:0002255	91.84	gold quality
skin of leg	UBERON:0001511	91.72	gold quality
skin of abdomen	UBERON:0001416	91.54	gold quality
monocyte	CL:0000576	91.34	gold quality
esophagus mucosa	UBERON:0002469	91.23	gold quality
lower esophagus mucosa	UBERON:0035834	91.10	gold quality
lower esophagus	UBERON:0013473	91.03	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.03	gold quality
ganglionic eminence	UBERON:0004023	90.98	gold quality
esophagus	UBERON:0001043	90.97	gold quality
leukocyte	CL:0000738	90.95	gold quality
left uterine tube	UBERON:0001303	90.86	gold quality
mononuclear cell	CL:0000842	90.70	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.45	gold quality
ectocervix	UBERON:0012249	90.23	gold quality
right coronary artery	UBERON:0001625	90.20	gold quality
mucosa of stomach	UBERON:0001199	90.04	gold quality
transverse colon	UBERON:0001157	89.85	gold quality
omental fat pad	UBERON:0010414	89.81	gold quality
peritoneum	UBERON:0002358	89.76	gold quality
body of uterus	UBERON:0009853	89.74	gold quality
spleen	UBERON:0002106	89.51	gold quality
mucosa of transverse colon	UBERON:0004991	89.50	gold quality
blood	UBERON:0000178	89.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.49	gold quality
upper lobe of left lung	UBERON:0008952	89.30	gold quality
body of stomach	UBERON:0001161	89.24	gold quality
apex of heart	UBERON:0002098	89.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting RAB35, 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-5692A	100.00	74.40	6850
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4492	99.87	68.25	3611
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-579-3P	99.86	71.66	3628

Literature-anchored findings (GeneRIF, showing 38)

• A Small Ras-like GTPase protein Ray was indicated to modulate p53 transcriptional activity of PRPK. (PMID:16600182)
• localized to the plasma membrane and endocytic compartments and controls a fast endocytic recycling pathway; plays an essential role during the terminal steps of cytokinesis (PMID:16950109)
• EPI64C and Rab35 regulate a recycling pathway in T cells and contribute to immunological synapse formation, most likely by participating in TCR transport to the immunological synapse (PMID:18450757)
• study found that Rab35 regulates the assembly of actin filaments in filopodia formation; effect was mediated by the actin-bundling protein fascin, which directly associated with active Rab35 (PMID:19729655)
• the phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) 5-phosphatase OCRL, which is mutated in Lowe syndrome patients, is an effector of the Rab35 GTPase in cytokinesis abscission (PMID:21706022)
• analysis of DENND1B-S complexed with its substrate Rab35 (PMID:22065758)
• whereas connecdenn 1 and 2 activate Rab35 for endosomal trafficking, connecdenn 3 uniquely activates Rab35 for its role in actin regulation (PMID:22072793)
• Activated ARF6 reduces Rab35 loading into the endocytic pathway. (PMID:22226746)
• mutual regulation with arf6 of cell adhesion and migration (PMID:23264734)
• Rab35 acts as a downstream target of Dvl2 and mediates cell migration. (PMID:23353182)
• Rab35 serves as a clathrin-mediated endocytosis detector. Loss of Rab35 input leads to elevated Arf6-GTP and shifts the sorting of clathrin-independent endocytosis cargo proteins to lysosomes. (PMID:25988331)
• the activation-inactivation cycles of Rab35 and ARF6 are required for the uptake of zymosan and that ACAP2 is an important component that links Rab35/ARF6 signaling during phagocytosis of zymosan. (PMID:26229970)
• Two somatic RAB35 mutations found in human tumors generate alleles that constitutively activate PI3K/AKT signaling, suppress apoptosis, and transform cells in a PI3K-dependent manner. (PMID:26338797)
• Authors propose that the precise spatial and temporal activation of Rab35 acts as a major switch for OCRL recruitment on newborn endosomes, post-scission PtdIns(4,5)P2 hydrolysis, and subsequent endosomal trafficking. (PMID:26725203)
• Short-term EGF stimulation if of lung tumor cells can increase the interaction between RUSC2 and GIT2, prolonged stimulation leads to a decrease of their interaction through activating Rab35. (PMID:27238570)
• Here the authors report that EspG interacts specifically with the small GTPases ARF6 and Rab35 during infection. (PMID:27261256)
• The involvement of Rab35 in diverse and apparently unrelated cellular functions can be explained by the central role of this GTPase in regulating phosphoinositides and F-actin, both on endosomes and at the plasma membrane[review]. (PMID:27329675)
• The results provide evidence that MICAL1 plays an essential role in the activation of ROS/Akt signaling and cell invasive phenotype and identify a novel link between RAB35 and MICAL1 in regulating breast cancer cell invasion. (PMID:27430308)
• This reference shows that the oxidoreductase MICAL1 is an effector of Rab35 during cytokinesis. (PMID:28230050)
• Data suggest that Rab35, interacting with TBC1D10A, functions in vascular endothelial cells as a negative regulator of histamine-evoked, Ca2+-dependent Weibel-Palade body exocytosis, most likely acting through the downstream effectors ACAP2 and Arf6. (Rab35 = rab GTP-binding protein 53; TBC1D10A = TBC1 domain family member 10A; ACAP2 = centaurin beta2; Arf6 = ADP-ribosylation factor 6) (PMID:28566286)
• The authors propose that Rab35-GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52. (PMID:28848034)
• A RAB35-p85/PI3K axis controls oscillatory apical protrusions required for efficient chemotactic migration. (PMID:29662076)
• The role of the oncogenic Rab35 in cancer invasion, metastasis, and immune evasion, especially in leukemia. (PMID:29781368)
• analysis of structural basis for effector recognition in Rab35/ACAP2 and Rab35/RUSC2 complexes (PMID:30905672)
• Study finds that RAB35 expression and localization are regulated by HOTAIR in hepatocellular carcinoma cells. (PMID:30943982)
• Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth. (PMID:32503983)
• An Arf/Rab cascade controls the growth and invasiveness of glioblastoma. (PMID:33443570)
• Rab11FIP1 maintains Rab35 at the intercellular bridge to promote actin removal and abscission. (PMID:34152390)
• Functional variant rs17525453 within RAB35 gene promoter is possibly associated with increased risk of Parkinson’s disease in Taiwanese population. (PMID:34275689)
• Rab35 regulates insulin secretion via phogrin in pancreatic beta cells. (PMID:34448213)
• MiR-185-5p targets RAB35 gene to regulate tumor cell-derived exosomes-mediated proliferation, migration and invasion of non-small cell lung cancer cells. (PMID:34500436)
• BAG3 Regulation of RAB35 Mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome Pathway and Tau Clearance. (PMID:35000752)
• Transcellular propagation of fibrillar alpha-synuclein from enteroendocrine to neuronal cells requires cell-to-cell contact and is Rab35-dependent. (PMID:35264710)
• Deubiquitylation of Rab35 by USP32 promotes the transmission of imatinib resistance by enhancing exosome secretion in gastrointestinal stromal tumours. (PMID:36725886)
• DENND2B activates Rab35 at the intercellular bridge, regulating cytokinetic abscission and tetraploidy. (PMID:37454296)
• This reference shows that MiniBAR/GARRE1 is a dual Rab35 and Rac1 effector during ciliogenesis. (PMID:37875118)
• A neurodevelopmental disorder associated with a loss-of-function missense mutation in RAB35. (PMID:38432637)
• Coxiella burnetii-containing vacuoles interact with host recycling endosomal proteins Rab11a and Rab35 for vacuolar expansion and bacterial growth. (PMID:38841112)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab35b	ENSDARG00000058425
mus_musculus	Rab35	ENSMUSG00000029518
rattus_norvegicus	Rab35	ENSRNOG00000022014

Paralogs (68): RAB27B (ENSG00000041353), RAB27A (ENSG00000069974), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB18 (ENSG00000099246), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB40AL (ENSG00000102128), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), 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-35 — Q15286 (reviewed: Q15286)

Alternative names: GTP-binding protein RAY, Ras-related protein Rab-1C

All UniProt accessions (3): Q15286, F5H157, F5H7F8

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. RAB35 is involved in the process of endocytosis and is an essential rate-limiting regulator of the fast recycling pathway back to the plasma membrane. During cytokinesis, required for the postfurrowing terminal steps, namely for intercellular bridge stability and abscission, possibly by controlling phosphatidylinositol 4,5-bis phosphate (PIP2) and SEPT2 localization at the intercellular bridge. May indirectly regulate neurite outgrowth. Together with TBC1D13 may be involved in regulation of insulin-induced glucose transporter SLC2A4/GLUT4 translocation to the plasma membrane in adipocytes.

Subunit / interactions. Interacts with DENND1A and DENND1B; in a nucleotide-dependent manner. Interacts with DENND1C; weak interaction which is nucleotide-independent. Interacts (GTP-bound form) with ACAP2, RUSC2, OCRL MICAL1 and MICALL1; the interaction is direct and probably recruits these effectors to membranes. Interacts with EHD1; the interaction is indirect through MICALL1 and probably recruits EHD1 to membranes. Interacts with GDI1, GDI2, CHM and CHML; phosphorylation at Thr-72 by LRRK2 disrupts these interactions.

Subcellular location. Cell membrane. Membrane. Clathrin-coated pit. Cytoplasmic vesicle. Clathrin-coated vesicle. Endosome. Melanosome.

Post-translational modifications. Phosphorylation at Thr-72 by LRRK2 prevents the association of regulatory proteins including CHM, CHML and GDP dissociation inhibitors GDI1 and GDI2. AMPylation at Tyr-77 by L.pneumophila DrrA occurs in the switch 2 region and leads to moderate inactivation of the GTPase activity. It appears to prolong the lifetime of the GTP state of RAB1B by restricting access of GTPase effectors to switch 2 and blocking effector-stimulated GTP hydrolysis, thereby rendering RAB35 constitutively active. Phosphocholinated by L.pneumophila AnkX. Both GDP-bound and GTP-bound forms can be phosphocholinated. Phosphocholination inhibits the GEF activity of DENND1A.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) including DENND1A, DENND1B and DENND1C which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) including TBC1D10 and TBC1D13 which increase 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 drives interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q15286-1	1	yes
Q15286-2	2

RefSeq proteins (2): NP_001161078, NP_006852* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041815	Rab35	Family
IPR050227	Rab	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (61 total): binding site 20, mutagenesis site 16, helix 9, strand 6, modified residue 3, short sequence motif 2, lipid moiety-binding region 2, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6IF3	X-RAY DIFFRACTION	1.5
6EKK	X-RAY DIFFRACTION	1.82
3TW8	X-RAY DIFFRACTION	2.1
6IF2	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15286-F1	89.18	0.70

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 (20): 34; 35; 37; 39; 40; 40; 63; 66; 120; 121; 123; 151 …

Post-translational modifications (5): 72, 75, 77, 200, 201

Mutagenesis-validated functional residues (16):

Position	Phenotype
4	decreased interaction with rusc2. no change in interaction with acap2, ocrl and mical1.
5	decreased interaction with rusc2.
10	loss of interaction with rusc2.
22	destabilization of the intercellular bridge during cytokinesis. strong reduction in fast recycling.
45	decreased interaction with acap2 and rusc2.
58	loss of interaction with rusc2.
60	decreased interaction with rusc2.
62	loss of interaction with acap2 and rusc2.
67	loss of gtpase activity. increased fast recycling.
72	loss of phosphorylation. no effect on binding to gdi1 and gdi2. loss of interaction with acap2. no change in interaction
72	loss of interaction with acap2. no change in interaction with rusc2.
72	phosphomimetic mutant. loss of binding to gdi1, gdi2, chm and chml. loss of interaction with acap2. no change in the int
76	decreased interaction with acap2.
79	loss of interaction with acap2 and rusc2.
79	decreased interaction with acap2 and rusc2.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8854214	TBC/RABGAPs
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 196 (showing top): GOBP_MITOTIC_CYTOKINESIS, ELVIDGE_HYPOXIA_DN, AAGCAAT_MIR137, MYOGENIN_Q6, TGCGCANK_UNKNOWN, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, AP2_Q3, REACTOME_MEMBRANE_TRAFFICKING, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_RESPONSE_TO_NERVE_GROWTH_FACTOR, GOBP_CYTOKINESIS, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION, GOCC_COATED_VESICLE, GOBP_MITOTIC_CELL_CYCLE

GO Biological Process (11): mitotic cytokinesis (GO:0000281), intracellular protein localization (GO:0008104), protein transport (GO:0015031), endosomal transport (GO:0016197), antigen processing and presentation (GO:0019882), neuron projection development (GO:0031175), endocytic recycling (GO:0032456), Rab protein signal transduction (GO:0032482), protein localization to endosome (GO:0036010), plasma membrane to endosome transport (GO:0048227), cellular response to nerve growth factor stimulus (GO:1990090)

GO Molecular Function (9): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), GDP binding (GO:0019003), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (15): cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), endosome membrane (GO:0010008), clathrin-coated endocytic vesicle membrane (GO:0030669), cell projection membrane (GO:0031253), melanosome (GO:0042470), intercellular bridge (GO:0045171), clathrin-coated endocytic vesicle (GO:0045334), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), endosome (GO:0005768), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Rab regulation of trafficking	2
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
vesicle-mediated transport	2
guanyl ribonucleotide binding	2
cytoplasm	2
membrane	2
endomembrane system	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
macromolecule localization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
intracellular transport	1
immune system process	1
neuron development	1
plasma membrane bounded cell projection organization	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
small GTPase-mediated signal transduction	1
protein localization to organelle	1
cellular response to growth factor stimulus	1
response to nerve growth factor	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
anion binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
clathrin-coated vesicle membrane	1

Protein interactions and networks

STRING

1996 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB35	DENND1B	Q6P3S1	995
RAB35	DENND1A	Q8TEH3	988
RAB35	ACAP2	Q15057	987
RAB35	TBC1D10A	Q9BXI6	987
RAB35	MADD	Q8WXG6	954
RAB35	OCRL	Q01968	943
RAB35	DENND1C	Q8IV53	930
RAB35	TBC1D10B	Q4KMP7	877
RAB35	FSCN1	Q16658	853
RAB35	PODXL	O00592	807
RAB35	MICAL1	Q8TDZ2	797
RAB35	TSG101	Q99816	780
RAB35	CLTC	Q00610	778
RAB35	MICALL1	Q8N3F8	767
RAB35	CALCOCO2	Q13137	719

IntAct

127 interactions, top by confidence:

A	B	Type	Score
CEP97	CCP110	psi-mi:“MI:2364”(proximity)	0.950
GDI1	RAB4A	psi-mi:“MI:0914”(association)	0.820
ALCAM	LGALS1	psi-mi:“MI:0914”(association)	0.770
CHM	RAB5C	psi-mi:“MI:0914”(association)	0.640
BTN3A2	BTN3A1	psi-mi:“MI:0914”(association)	0.600
RAB35	DNM2	psi-mi:“MI:0915”(physical association)	0.560
RAB35	JPH3	psi-mi:“MI:0915”(physical association)	0.560
HTT	RAB35	psi-mi:“MI:0915”(physical association)	0.560
CD63	LGALS8	psi-mi:“MI:0914”(association)	0.530
RAB35	MICALL1	psi-mi:“MI:0915”(physical association)	0.510
	RAB1A	psi-mi:“MI:0915”(physical association)	0.400
PLEKHN1	RAB35	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
MAPRE1	CTNNB1	psi-mi:“MI:0914”(association)	0.350
RAB10	RAB19	psi-mi:“MI:0914”(association)	0.350
SPHK1	MYO1C	psi-mi:“MI:0914”(association)	0.350
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350

BioGRID (640): RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), RAB35 (Proximity Label-MS), RAB35 (Proximity Label-MS), RAB35 (Proximity Label-MS), RAB35 (Proximity Label-MS), RAB35 (Proximity Label-MS), RAB35 (Proximity Label-MS), RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), RAB35 (Affinity Capture-MS)

ESM2 similar proteins: A4FV54, F1PTE3, P17609, P20790, P20791, P22127, P22128, P24409, P34140, P35280, P35281, P35286, P35293, P51153, P55258, P61006, P61007, P61026, P61027, P61028, P70550, Q05976, Q0IIG8, Q15286, Q2HJI8, Q39571, Q4R5P1, Q54DA7, Q54NU2, Q559X6, Q55FK2, Q58DS5, Q5EB77, Q5F470, Q5KTJ6, Q5R4A3, Q5R5H5, Q5R5U1, Q5REC9, Q5U316

Diamond homologs: A2WSI7, A2Y7R5, A2YEQ6, H9BW96, O17915, O76742, O97572, P09527, P18067, P22127, P24408, P24409, P28748, P32835, P32836, P33519, P34139, P35288, P36411, P36864, P38542, P38543, P38544, P38545, P38546, P38547, P38548, P41914, P41915, P41916, P41917, P41918, P41919, P42558, P51149, P51150, P51151, P52301, P54765, P54766

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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
RAB geranylgeranylation	7	10.4×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting to membrane	6	12.8×	5e-03
endocytosis	9	6.2×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1030 predictions. Top by Δscore:

Variant	Effect	Δscore
12:120097369:AACAT:A	acceptor_gain	1.0000
12:120097370:ACAT:A	acceptor_gain	1.0000
12:120097371:CAT:C	acceptor_gain	1.0000
12:120097371:CATC:C	acceptor_gain	1.0000
12:120097372:AT:A	acceptor_gain	1.0000
12:120097373:TCTG:T	acceptor_loss	1.0000
12:120097374:C:CC	acceptor_gain	1.0000
12:120097375:T:G	acceptor_loss	1.0000
12:120097376:G:C	acceptor_gain	1.0000
12:120098805:CCTCA:C	donor_loss	1.0000
12:120098806:CTCA:C	donor_loss	1.0000
12:120098807:TCAC:T	donor_loss	1.0000
12:120098808:CACC:C	donor_loss	1.0000
12:120098809:A:AC	donor_gain	1.0000
12:120098809:ACCTC:A	donor_loss	1.0000
12:120098810:C:CC	donor_gain	1.0000
12:120098810:C:G	donor_loss	1.0000
12:120098810:CCT:C	donor_gain	1.0000
12:120098931:ACCCA:A	acceptor_gain	1.0000
12:120098932:CCCA:C	acceptor_gain	1.0000
12:120098932:CCCAC:C	acceptor_gain	1.0000
12:120098933:CCA:C	acceptor_gain	1.0000
12:120098933:CCAC:C	acceptor_gain	1.0000
12:120098934:C:T	acceptor_gain	1.0000
12:120098934:CA:C	acceptor_gain	1.0000
12:120098934:CAC:C	acceptor_gain	1.0000
12:120098936:C:CC	acceptor_gain	1.0000
12:120098939:C:CT	acceptor_gain	1.0000
12:120099025:CTCAC:C	donor_loss	1.0000
12:120099027:CAC:C	donor_loss	1.0000

AlphaMissense

1339 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:120098836:G:T	A151D	1.000
12:120098838:G:C	S150R	1.000
12:120098838:G:T	S150R	1.000
12:120098840:T:G	S150R	1.000
12:120098925:C:A	K121N	1.000
12:120098925:C:G	K121N	1.000
12:120098927:T:C	K121E	1.000
12:120098928:A:C	N120K	1.000
12:120098928:A:T	N120K	1.000
12:120098932:C:T	G119D	1.000
12:120099074:A:G	L103P	1.000
12:120099076:C:A	W102C	1.000
12:120099076:C:G	W102C	1.000
12:120099078:A:G	W102R	1.000
12:120099078:A:T	W102R	1.000
12:120099134:C:T	G83E	1.000
12:120099135:C:A	G83W	1.000
12:120099135:C:G	G83R	1.000
12:120099135:C:T	G83R	1.000
12:120103835:A:C	I73S	1.000
12:120103835:A:T	I73N	1.000
12:120103841:C:G	R71P	1.000
12:120103843:G:C	F70L	1.000
12:120103843:G:T	F70L	1.000
12:120103844:A:C	F70C	1.000
12:120103844:A:G	F70S	1.000
12:120103845:A:C	F70V	1.000
12:120103845:A:G	F70L	1.000
12:120103845:A:T	F70I	1.000
12:120103856:C:A	G66V	1.000

dbSNP variants (sampled 300 via entrez): RS1000121048 (12:120094819 G>A), RS1000329592 (12:120100004 G>A), RS1000473461 (12:120105259 G>A,C), RS1000527192 (12:120104923 C>A,G,T), RS1000692820 (12:120116818 C>G), RS1000702873 (12:120116227 C>T), RS1000712544 (12:120118684 TC>T), RS1000944728 (12:120110554 T>A,G), RS1001000140 (12:120117199 C>G,T), RS1001158735 (12:120107956 C>T), RS1001201791 (12:120102657 C>G), RS1001209611 (12:120107794 G>A), RS1001251792 (12:120109056 C>T), RS1001490828 (12:120098615 G>A), RS1001578514 (12:120099860 G>A)

Disease associations

OMIM: gene MIM:604199 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal recessive
familial hypercholesterolemia	Limited	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (3): complex neurodevelopmental disorder (MONDO:0100038), familial hypercholesterolemia (MONDO:0005439), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006979_1084	Heel bone mineral density	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067195 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.63	Kd	235.3	nM	CHEMBL5653589
6.63	ED50	235.3	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149174: Binding affinity to human RAB35 incubated for 45 mins by Kinobead based pull down assay	kd	0.2353	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
ochratoxin A	affects binding	1
benzo(e)pyrene	increases methylation	1
tamibarotene	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tretinoin	affects expression	1
Urethane	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652216	Binding	Binding affinity to human RAB35 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2D3	Abcam HeLa RAB35 KO	Cancer cell line	Female
CVCL_TI15	HAP1 RAB35 (-) 1	Cancer cell line	Male
CVCL_XS10	HAP1 RAB35 (-) 2	Cancer cell line	Male
CVCL_XS11	HAP1 RAB35 (-) 3	Cancer cell line	Male
CVCL_XS12	HAP1 RAB35 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00655265	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Patients With Familial Hypercholesterolaemia Taking Colesevelam as add-on Therapy to Their Existing Medication
NCT00916643	PHASE4	COMPLETED	Low-Density Lipoprotein (LDL) Apheresis Using H.E.L.P. Therapy
NCT03331666	PHASE4	TERMINATED	Impact of LDL-cholesterol Lowering on Platelet Activation
NCT05465278	PHASE4	COMPLETED	Alirocumab and Plaque Burden In Familial Hypercholesterolaemia
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00355615	PHASE3	COMPLETED	PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
NCT00552097	PHASE3	COMPLETED	Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578)
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00827606	PHASE3	COMPLETED	Atorvastatin Three Year Pediatric Study
NCT00943306	PHASE3	COMPLETED	Long Term, Follow-on Study of Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT01813006	PHASE3	COMPLETED	Effect of Omega-3 Fatty Acid on Endothelial Function
NCT01841684	PHASE3	TERMINATED	Efficacy and Tolerability of Anacetrapib Added to Ongoing Lipid-Lowering Therapy in Adult Participants With Homozygous Familial Hypercholesterolemia (HoFH) (MK-0859-042)
NCT02624869	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)
NCT02748057	PHASE3	COMPLETED	A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-833)
NCT03884452	PHASE3	COMPLETED	Ezetimibe (SCH 58235) Taken With Either Atorvastatin or Simvastatin in Participants With Familial Hypercholesterolemia (MK-0653-018)
NCT04798430	PHASE3	ENROLLING_BY_INVITATION	Long-term Efficacy and Safety of OLE LIB003 in HoFH, HeFH, and High-risk CVD Patients Requiring Further LDL-C Reduction
NCT05142722	PHASE3	COMPLETED	Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT05238519	PHASE3	ACTIVE_NOT_RECRUITING	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05952856	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids
NCT05952869	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)
NCT06005597	PHASE3	COMPLETED	Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00079846	PHASE2	TERMINATED	Implitapide in Patients With Homozygous Familial Hypercholesterolemia (HoFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00079859	PHASE2	TERMINATED	Implitapide in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00477594	PHASE2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT00751608	PHASE2	WITHDRAWN	Effect of APL180 on Endothelial Function in Familial Hypercholesterolemia Patients
NCT02597127	PHASE2	COMPLETED	Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)
NCT03060577	PHASE2	COMPLETED	An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol
NCT04455581	PHASE2	UNKNOWN	A Study to Determine the Safety, Tolerability, and Efficacy of SHR-1209 in Patients With Familial Hypercholesterolemia
NCT04941599	PHASE2	RECRUITING	2-Hydroxybenzylamine (2-HOBA) to Reduce HDL Modification and Improve HDL Function in Familial Hypercholesterolemia (FH)
NCT05261126	PHASE2	COMPLETED	A Study of the Efficacy and Safety of Enclitide Chloride (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-008)
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders