RAB3GAP1

Summary

RAB3GAP1 (RAB3 GTPase activating protein catalytic subunit 1, HGNC:17063) is a protein-coding gene on chromosome 2q21.3, encoding Rab3 GTPase-activating protein catalytic subunit (Q15042). Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.

This gene encodes the catalytic subunit of a Rab GTPase activating protein. The encoded protein forms a heterodimer with a non-catalytic subunit to specifically regulate the activity of members of the Rab3 subfamily of small G proteins. This protein mediates the hydrolysis of GTP bound Rab3 to the GDP bound form. Mutations in this gene are associated with Warburg micro syndrome. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 22930 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Warburg micro syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 642 total — 59 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 95
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_012233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17063
Approved symbol	RAB3GAP1
Name	RAB3 GTPase activating protein catalytic subunit 1
Location	2q21.3
Locus type	gene with protein product
Status	Approved
Aliases	RAB3GAP, KIAA0066, RAB3GAP130, WARBM1
Ensembl gene	ENSG00000115839
Ensembl biotype	protein_coding
OMIM	602536
Entrez	22930

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 12 nonsense_mediated_decay, 11 retained_intron, 9 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000264158, ENST00000425393, ENST00000442034, ENST00000487003, ENST00000489858, ENST00000497080, ENST00000539493, ENST00000684914, ENST00000685652, ENST00000685874, ENST00000685967, ENST00000686114, ENST00000686403, ENST00000687199, ENST00000687630, ENST00000688088, ENST00000688182, ENST00000689187, ENST00000689880, ENST00000690208, ENST00000690785, ENST00000691339, ENST00000691478, ENST00000692993, ENST00000693554, ENST00000713848, ENST00000713849, ENST00000713850, ENST00000713851, ENST00000713852, ENST00000855134, ENST00000855135, ENST00000855136, ENST00000855137, ENST00000970735

RefSeq mRNA: 2 — MANE Select: NM_012233 NM_001172435, NM_012233

CCDS: CCDS33294, CCDS54402

Canonical transcript exons

ENST00000264158 — 24 exons

Exon	Start	End
ENSE00003460724	135135564	135135932
ENSE00003462334	135153649	135153876
ENSE00003491810	135120819	135120918
ENSE00003494263	135093615	135093693
ENSE00003497854	135132895	135132984
ENSE00003502789	135058011	135058086
ENSE00003515208	135133861	135134033
ENSE00003523238	135113151	135113270
ENSE00003553748	135162555	135162651
ENSE00003584523	135115216	135115381
ENSE00003593726	135162748	135162851
ENSE00003593795	135124165	135124246
ENSE00003602266	135129995	135130087
ENSE00003610726	135126181	135126249
ENSE00003615359	135090998	135091130
ENSE00003618966	135130552	135130721
ENSE00003619183	135052430	135052485
ENSE00003636540	135135265	135135319
ENSE00003637922	135150369	135150506
ENSE00003664368	135126583	135126656
ENSE00003668873	135164594	135164696
ENSE00003691432	135162986	135163101
ENSE00004021567	135052292	135052325
ENSE00004021571	135168545	135170710

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.1654 / max 509.6753, expressed in 1815 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22634	37.8089	1815
22635	0.1608	57
22637	0.1193	57
22636	0.0764	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hair follicle	UBERON:0002073	99.23	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.77	gold quality
secondary oocyte	CL:0000655	98.73	gold quality
endothelial cell	CL:0000115	98.48	gold quality
middle temporal gyrus	UBERON:0002771	98.41	gold quality
cervix squamous epithelium	UBERON:0006922	98.28	gold quality
visceral pleura	UBERON:0002401	98.24	gold quality
tibia	UBERON:0000979	98.16	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.04	gold quality
parietal pleura	UBERON:0002400	98.00	gold quality
pleura	UBERON:0000977	97.92	gold quality
entorhinal cortex	UBERON:0002728	97.85	gold quality
substantia nigra pars compacta	UBERON:0001965	97.78	gold quality
squamous epithelium	UBERON:0006914	97.73	gold quality
blood vessel layer	UBERON:0004797	97.69	gold quality
parietal lobe	UBERON:0001872	97.66	gold quality
tongue squamous epithelium	UBERON:0006919	97.66	gold quality
orbitofrontal cortex	UBERON:0004167	97.64	gold quality
postcentral gyrus	UBERON:0002581	97.62	gold quality
esophagus squamous epithelium	UBERON:0006920	97.62	gold quality
saphenous vein	UBERON:0007318	97.56	gold quality
superior vestibular nucleus	UBERON:0007227	97.55	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.53	gold quality
urethra	UBERON:0000057	97.45	gold quality
cauda epididymis	UBERON:0004360	97.44	gold quality
CA1 field of hippocampus	UBERON:0003881	97.37	gold quality
ventral tegmental area	UBERON:0002691	97.33	gold quality
gingival epithelium	UBERON:0001949	97.27	gold quality
germinal epithelium of ovary	UBERON:0001304	97.26	gold quality
gluteal muscle	UBERON:0002000	97.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

53 targeting RAB3GAP1, 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-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-8485	100.00	77.57	4731
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-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-2115-3P	99.31	69.68	2026

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• RAB3GAP1 has been shown to cause Micro syndrome. (PMID:18286824)
• study found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds (PMID:20512159)
• Mutation in RAB3GAP1 is associated with warburg micro syndrome. (PMID:22768674)
• The RAB3GAP gene encodes a protein which is a key regulator of the Rab3 pathway implicated in exocytic release of ocular and neurodevleopmental trophic factors. (PMID:22876574)
• 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)
• Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility. (PMID:23593153)
• This replication and meta-analysis study showed that genetic variation upstream of the RAB3GAP1 gene is highly likely to be a contributor to the genetic risk of keratoconus development. (PMID:23833071)
• Rab18 and a Rab18 GEF complex of Rab3GAP1 and Rab3GAP2 have roles in the endoplasmic reticulum structure (PMID:24891604)
• The stage catalyzed by Rab3 is in a unidirectional, hierarchical connection in which the intra-acrosomal calcium mobilization arm was subordinated to the fusion protein arm; somewhere after Rab3, the pathways became independent. (PMID:25159528)
• A large intragenic homozygous RAB3GAP1 microdeletion is associated with Warburg micro syndrome 1. (PMID:25332050)
• RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy (PMID:25495476)
• results suggest that the binding of vesicle-associated membrane protein-associated protein B(VAP-B) to Rab3 GTPase activating protein (Rab3GAP1) is implicated in the regulation of nuclear envelope formation through ER-Golgi intermediate compartment (PMID:25612670)
• Warburg Micro syndrome is caused by RAB3GAP deficiency. (PMID:26063829)
• Homozygosity mapping using single nucleotide polymorphism (SNP) microarray data to identify the causative gene in a case with Warburg Micro syndrome (WARBM). (PMID:26138576)
• sequencing of RAB3GAP1 revealed novel compound heterozygous mutations in the siblings: a paternally inherited missense mutation (c.560G>C; p.Arg187Pro) in exon 7 and a maternally derived nonsense mutation (c.1009C>T; p.Arg337Ter) in exon 12. (PMID:26421802)
• Whole-exome sequencing, using DNA of the first fetus, was performed shortly after the birth of a male child, and two truncating RAB3GAP1 mutations were detected: c.538G>T; p. (Glu180*) and c.943C>T; p. (Arg315*). (PMID:27256633)
• RAB18 modulates macroautophagy and proteostasis, and is dependent on activity of RAB3GAP1 and RAB3GAP2. (PMID:28342870)
• show that FOXC1 regulates the expression of RAB3GAP1, RAB3GAP2 and SNAP25 (PMID:28575017)
• overexpressing p130 or E2F4 significantly improved migration but not proliferation of mMSCs. Our data suggest that cell cycle regulation may be involved in p130/E2F4-mediated changes in the multipotential abilities of bone-marrow-derived mesenchymal stem cells (MSCs). (PMID:29987913)
• Mutations in RAB3GAP1 gene are associated with Martsolf and Warburg micro syndromes. (PMID:30730599)
• Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights. (PMID:32740904)
• [Analysis of a case of Warburg micro syndrome type 1 due to variant of RAB3GAP1 gene]. (PMID:33306828)
• Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report. (PMID:33910511)
• Proteasomal degradation of p130 facilitate cell cycle deregulation and impairment of cellular differentiation in high-risk Human Papillomavirus 16 and 18 E7 transfected cells. (PMID:34169395)
• Exome sequencing identifies a novel pathogenic variant in RAB3GAP1 causing Warburg Micro syndrome in a Pakistani family. (PMID:37186309)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab3gap1	ENSDARG00000098079
mus_musculus	Rab3gap1	ENSMUSG00000036104
rattus_norvegicus	Rab3gap1	ENSRNOG00000003953
drosophila_melanogaster	Rab3GAP1	FBGN0051935
caenorhabditis_elegans		WBGENE00004317

Protein

Protein identifiers

Rab3 GTPase-activating protein catalytic subunit — Q15042 (reviewed: Q15042)

Alternative names: RAB3 GTPase-activating protein 130 kDa subunit, Rab3-GAP p130

All UniProt accessions (15): Q15042, A0A8I5KRB1, A0A8I5KRH8, A0A8I5KSB6, A0A8I5KT44, A0A8I5KW23, A0A8I5KWG9, A0A8J9AUI2, A0AAQ5BGZ4, A0AAQ5BGZ6, A0AAQ5BH25, A0AAQ5BH27, A0AAQ5BH49, B9A6J2, C9J1R5

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins. Has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43. Additionally, it has guanine nucleotide exchange factor (GEF) activity towards RAB18, promoting GDP release from RAB18 and the conversion of inactive RAB18-GDP to the active form RAB18-GTP. Recruits and stabilizes RAB18 at the cis-Golgi membrane in fibroblasts where RAB18 is most likely activated. Also involved in RAB18 recruitment at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure. Required for normal eye and brain development. May participate in neurodevelopmental processes such as cell proliferation, migration and differentiation before synapse formation, and is involved in regulating non-synaptic vesicular release of neurotransmitters.

Subunit / interactions. The Rab3 GTPase-activating complex is a heterodimer composed of RAB3GAP1 and RAB3GAP2. The Rab3 GTPase-activating complex interacts with DMXL2. Interacts with LMAN1.

Subcellular location. Cytoplasm. Endoplasmic reticulum. Golgi apparatus. cis-Golgi network.

Tissue specificity. Ubiquitous.

Disease relevance. Warburg micro syndrome 1 (WARBM1) [MIM:600118] A rare, autosomal recessive 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. Martsolf syndrome 2 (MARTS2) [MIM:619420] An autosomal recessive disorder characterized by congenital cataracts, mildly to severely impaired intellectual development, and facial dysmorphism. Other features include brain malformations, microcephaly, and hypogonadism-hypogenitalism. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Rab3-GAP catalytic subunit family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15042-1	1	yes
Q15042-3	2
Q15042-4	3

RefSeq proteins (2): NP_001165906, NP_036365* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026147	Rab3GAP1_conserved	Domain
IPR045698	Rab3GAP1_C	Domain
IPR045700	Rab3GAP1	Family

Pfam: PF13890, PF19533

UniProt features (23 total): modified residue 8, mutagenesis site 5, splice variant 3, sequence variant 3, region of interest 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8VYB	ELECTRON MICROSCOPY	3.37

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15042-F1	78.46	0.47

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 (8): 664, 908, 83, 379, 537, 579, 581, 590

Mutagenesis-validated functional residues (5):

Position	Phenotype
618–748	loss of gap activity towards rab3a. retains gef activity towards rab18.
619	no effect.
700	no effect.
728	loss of gap activity.
753	no effect.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

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

MSigDB gene sets: 447 (showing top): GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_GLUTAMATE_SECRETION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_BODY_MORPHOGENESIS, GOBP_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_SHORT_TERM_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (16): brain development (GO:0007420), hypothalamus development (GO:0021854), Rab protein signal transduction (GO:0032482), lipid droplet organization (GO:0034389), camera-type eye development (GO:0043010), regulation of short-term neuronal synaptic plasticity (GO:0048172), excitatory postsynaptic potential (GO:0060079), face morphogenesis (GO:0060325), positive regulation of glutamate neurotransmitter secretion in response to membrane depolarization (GO:0061646), establishment of protein localization to endoplasmic reticulum membrane (GO:0097051), positive regulation of protein lipidation (GO:1903061), regulation of calcium ion-dependent exocytosis of neurotransmitter (GO:1903233), positive regulation of endoplasmic reticulum tubular network organization (GO:1903373), positive regulation of autophagosome assembly (GO:2000786), regulation of GTPase activity (GO:0043087), positive regulation of GTPase activity (GO:0043547)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (11): endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cis-Golgi network (GO:0005801), lipid droplet (GO:0005811), cytosol (GO:0005829), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), endoplasmic reticulum tubular network (GO:0071782), postsynapse (GO:0098794), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Golgi-to-ER retrograde transport	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTPase activity	3
cytoplasm	3
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
GTPase regulator activity	2
endoplasmic reticulum subcompartment	2
endomembrane system	2
central nervous system development	1
animal organ development	1
head development	1
diencephalon development	1
limbic system development	1
anatomical structure development	1
small GTPase-mediated signal transduction	1
organelle organization	1
eye development	1
regulation of neuronal synaptic plasticity	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
anatomical structure morphogenesis	1
head morphogenesis	1
face development	1
cellular response to stimulus	1
positive regulation of glutamate secretion, neurotransmission	1
establishment of protein localization to endoplasmic reticulum	1
establishment of protein localization to membrane	1
protein lipidation	1
positive regulation of protein modification process	1
positive regulation of lipoprotein metabolic process	1
regulation of protein lipidation	1
regulation of calcium ion-dependent exocytosis	1
calcium ion-regulated exocytosis of neurotransmitter	1
regulation of synaptic vesicle exocytosis	1
positive regulation of organelle organization	1
endoplasmic reticulum tubular network organization	1
regulation of endoplasmic reticulum tubular network organization	1
autophagosome assembly	1
positive regulation of macroautophagy	1
positive regulation of vacuole organization	1
positive regulation of organelle assembly	1

Protein interactions and networks

STRING

1712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB3GAP1	RAB3GAP2	Q9H2M9	997
RAB3GAP1	RAB3A	P20336	884
RAB3GAP1	DMXL2	Q8TDJ6	868
RAB3GAP1	RAB18	Q9NP72	863
RAB3GAP1	MADD	Q8WXG6	838
RAB3GAP1	RASA1	P20936	813
RAB3GAP1	TBC1D20	Q96BZ9	766
RAB3GAP1	DMXL1	Q9Y485	682
RAB3GAP1	VAPB	O95292	577
RAB3GAP1	VSX1	Q9NZR4	575
RAB3GAP1	SCOC	Q9UIL1	561
RAB3GAP1	ZNF469	Q96JG9	550
RAB3GAP1	WDR44	Q5JSH3	523
RAB3GAP1	DOCK9	Q9BZ29	520
RAB3GAP1	ARHGEF10	O15013	520

IntAct

119 interactions, top by confidence:

A	B	Type	Score
BRAF	HRAS	psi-mi:“MI:0914”(association)	0.940
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
RAB3GAP2	VAPB	psi-mi:“MI:0914”(association)	0.730
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
COG7	ILVBL	psi-mi:“MI:0914”(association)	0.640
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
VAPA	PITPNM1	psi-mi:“MI:0914”(association)	0.640
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
BTN2A1	POTEF	psi-mi:“MI:0914”(association)	0.530
BCAT1	ARNT	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
PSMC4	PSMD3	psi-mi:“MI:0914”(association)	0.530
GMFB	GMFG	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
RAB3GAP1	AP2B1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (208): RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Co-fractionation), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Proximity Label-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS), RAB3GAP1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMD0, A1A535, A1ZAB5, A2AIV2, A8E7C5, A8PJX4, A8XAA9, B0W2S0, B3MIW0, B3NPV8, B4GAM1, B4JW99, B4KT50, B4LQ23, B4MY63, B4P6P7, D3YVL2, E9PXF8, F4HS99, F4HZK4, F4J5S1, F4JKH6, O60502, O75153, O88379, P34466, P69735, Q0IHW8, Q0VA04, Q15042, Q17N71, Q291J5, Q5PQS3, Q5SW19, Q5TYW4, Q5U430, Q69YN4, Q6NTN5, Q6ZT12, Q7PZD5

Diamond homologs: P69735, Q15042, Q642R9, Q6NUV0, Q80UJ7, Q9VQ26

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RAB3GAP1	“down-regulates activity”	RAB3A	“gtpase-activating protein”
DMXL2	“up-regulates quantity”	RAB3GAP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 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
Degradation of CRY and PER proteins	6	12.7×	5e-03
Downstream TCR signaling	7	8.6×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of MAPK cascade	10	6.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	18
Uncertain significance	254
Likely benign	195
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100769	NM_012233.3(RAB3GAP1):c.899+1G>A	Pathogenic
100770	NM_012233.3(RAB3GAP1):c.2037_2055dup (p.Phe686fs)	Pathogenic
100771	NM_012233.3(RAB3GAP1):c.52A>C (p.Thr18Pro)	Pathogenic
100772	NM_012233.3(RAB3GAP1):c.71A>T (p.Glu24Val)	Pathogenic
1047919	NM_012233.3(RAB3GAP1):c.1552C>T (p.Gln518Ter)	Pathogenic
1073466	NM_012233.3(RAB3GAP1):c.107_114del (p.Asp36fs)	Pathogenic
1176759	GRCh37/hg19 2q21.3(chr2:135848568-135891603)x1	Pathogenic
1177055	NM_012233.3(RAB3GAP1):c.2607-1G>C	Pathogenic
1177056	NM_012233.3(RAB3GAP1):c.2187_2188delinsCT (p.Met729_Lys730delinsIleTer)	Pathogenic
1338882	NM_012233.3(RAB3GAP1):c.691C>T (p.Arg231Ter)	Pathogenic
1453806	NC_000002.11:g.(?135888102)(135926351_?)del	Pathogenic
1457485	NM_012233.3(RAB3GAP1):c.1417_1423del (p.Gly473fs)	Pathogenic
1698016	NM_012233.3(RAB3GAP1):c.519G>A (p.Trp173Ter)	Pathogenic
1802019	NM_012233.3(RAB3GAP1):c.72_73del (p.Arg25fs)	Pathogenic
191126	NM_012233.3(RAB3GAP1):c.1009C>T (p.Arg337Ter)	Pathogenic
2028577	NM_012233.3(RAB3GAP1):c.2167G>T (p.Gly723Ter)	Pathogenic
2049610	NM_012233.3(RAB3GAP1):c.659del (p.Pro219_Leu220insTer)	Pathogenic
211979	NM_012233.3(RAB3GAP1):c.2642T>G (p.Leu881Ter)	Pathogenic
2425782	NC_000002.11:g.(?135920105)(135920691_?)del	Pathogenic
2438030	NM_012233.3(RAB3GAP1):c.1174C>T (p.Arg392Ter)	Pathogenic
2444049	NM_012233.3(RAB3GAP1):c.1440_1441del (p.Trp481fs)	Pathogenic
2574155	NM_012233.3(RAB3GAP1):c.2853C>G (p.Tyr951Ter)	Pathogenic
2628349	NM_012233.3(RAB3GAP1):c.1247del (p.Pro416fs)	Pathogenic
285763	NM_012233.3(RAB3GAP1):c.612del (p.Leu205fs)	Pathogenic
285764	NM_012233.3(RAB3GAP1):c.475_478del (p.Thr159fs)	Pathogenic
3061955	NM_012233.3(RAB3GAP1):c.2710-1G>A	Pathogenic
3242259	NM_012233.3(RAB3GAP1):c.2709+1G>T	Pathogenic
3247542	NC_000002.11:g.(?135809878)(135926351_?)del	Pathogenic
3247543	NC_000002.11:g.(?135809878)(135810075_?)del	Pathogenic
3378402	NM_012233.3(RAB3GAP1):c.120del (p.Ile40fs)	Pathogenic

SpliceAI

4025 predictions. Top by Δscore:

Variant	Effect	Δscore
2:135052486:G:C	donor_loss	1.0000
2:135052486:G:GG	donor_gain	1.0000
2:135090984:ATT:A	acceptor_gain	1.0000
2:135090986:T:A	acceptor_gain	1.0000
2:135090994:ATAG:A	acceptor_gain	1.0000
2:135091127:GAGG:G	donor_gain	1.0000
2:135091128:AGGGT:A	donor_loss	1.0000
2:135091129:GG:G	donor_gain	1.0000
2:135091130:GG:G	donor_gain	1.0000
2:135091131:GTA:G	donor_loss	1.0000
2:135091132:T:TT	donor_loss	1.0000
2:135093614:GAT:G	acceptor_gain	1.0000
2:135093690:GATG:G	donor_gain	1.0000
2:135096229:G:GT	donor_gain	1.0000
2:135113266:GGCTG:G	donor_gain	1.0000
2:135113267:GCTG:G	donor_gain	1.0000
2:135113267:GCTGG:G	donor_gain	1.0000
2:135113269:TGG:T	donor_loss	1.0000
2:135113271:G:GC	donor_loss	1.0000
2:135113272:T:A	donor_loss	1.0000
2:135114616:T:G	donor_gain	1.0000
2:135115378:GATT:G	donor_gain	1.0000
2:135115382:G:GG	donor_gain	1.0000
2:135120440:A:T	donor_gain	1.0000
2:135120807:T:G	acceptor_gain	1.0000
2:135120818:GGGAT:G	acceptor_gain	1.0000
2:135124163:A:AG	acceptor_gain	1.0000
2:135124164:G:GA	acceptor_gain	1.0000
2:135124164:GA:G	acceptor_gain	1.0000
2:135124164:GAC:G	acceptor_gain	1.0000

AlphaMissense

6432 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:135052445:T:C	F12L	1.000
2:135052447:T:A	F12L	1.000
2:135052447:T:G	F12L	1.000
2:135052452:T:C	I14T	1.000
2:135052460:T:C	F17L	1.000
2:135052461:T:G	F17C	1.000
2:135052462:C:A	F17L	1.000
2:135052462:C:G	F17L	1.000
2:135126203:T:A	W285R	1.000
2:135126203:T:C	W285R	1.000
2:135126611:T:A	W310R	1.000
2:135126611:T:C	W310R	1.000
2:135135922:C:A	P638Q	1.000
2:135150481:T:C	L679P	1.000
2:135150490:A:G	D682G	1.000
2:135150502:T:C	F686S	1.000
2:135150506:G:C	K687N	1.000
2:135150506:G:T	K687N	1.000
2:135153653:C:A	A689D	1.000
2:135153679:T:C	F698L	1.000
2:135153680:T:C	F698S	1.000
2:135153681:T:A	F698L	1.000
2:135153681:T:G	F698L	1.000
2:135153688:T:A	W701R	1.000
2:135153688:T:C	W701R	1.000
2:135153704:A:C	D706A	1.000
2:135153773:T:C	M729T	1.000
2:135153793:T:A	W736R	1.000
2:135153793:T:C	W736R	1.000
2:135153795:G:C	W736C	1.000

dbSNP variants (sampled 300 via entrez): RS1000000079 (2:135092644 A>G), RS1000043566 (2:135076694 A>T), RS1000066400 (2:135142457 C>T), RS1000069229 (2:135162660 C>A,T), RS1000070052 (2:135094523 C>G,T), RS1000102019 (2:135085634 G>C), RS1000167463 (2:135173197 T>C), RS1000183436 (2:135115181 C>A,T), RS1000217724 (2:135129144 CCT>C), RS1000231037 (2:135083746 T>G), RS1000297452 (2:135149896 A>G,T), RS1000307681 (2:135076178 G>A,C), RS1000308480 (2:135067713 T>C), RS1000318127 (2:135115738 G>A), RS1000324460 (2:135060450 C>T)

Disease associations

OMIM: gene MIM:602536 | disease phenotypes: MIM:600118, MIM:619420, MIM:212720, MIM:219050

GenCC curated gene-disease

Disease	Classification	Inheritance
Warburg micro syndrome	Definitive	Autosomal recessive
Warburg micro syndrome 1	Definitive	Autosomal recessive
cataract-intellectual disability-hypogonadism syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Warburg micro syndrome	Definitive	AR

Mondo (11): Warburg micro syndrome 1 (MONDO:0010822), Warburg micro syndrome (MONDO:0016649), Martsolf syndrome 2 (MONDO:0030376), amenorrhea (MONDO:0001836), Martsolf syndrome (MONDO:0023910), movement disorder (MONDO:0005395), congenital ptosis (MONDO:0008340), cryptorchidism (MONDO:0009047), cleft palate (MONDO:0016064), hypertrichosis (MONDO:0019280), (MONDO:0008929)

Orphanet (5): Micro syndrome (Orphanet:2510), Cataract-intellectual disability-hypogonadism syndrome (Orphanet:1387), Cleft palate (Orphanet:2014), Rare disorder with hypertrichosis (Orphanet:79365), Congenital ptosis (Orphanet:91411)

HPO phenotypes

95 total (30 of 95 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000126	Hydronephrosis
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000221	Furrowed tongue
HP:0000232	Everted lower lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000480	Retinal coloboma
HP:0000482	Microcornea
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000568	Microphthalmia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000760_28	Cholesterol, total	1.000000e-08
GCST001261_2	Corneal structure	1.000000e-09
GCST002221_34	Cholesterol, total	1.000000e-13
GCST002783_168	Body mass index	2.000000e-06
GCST002783_222	Body mass index	1.000000e-06
GCST002896_26	Cholesterol, total	3.000000e-09
GCST008075_201	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	8.000000e-06
GCST008077_73	LDL cholesterol levels	2.000000e-08
GCST008078_109	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-13
GCST008078_28	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-10
GCST008079_159	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-13
GCST008079_62	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	9.000000e-10
GCST008086_30	LDL cholesterol levels in current drinkers	1.000000e-06
GCST008086_63	LDL cholesterol levels in current drinkers	7.000000e-10
GCST010089_1	Sudden cardiac arrest in coronary artery disease	5.000000e-12
GCST010397_12	Gut microbiota (bacterial taxa, rank normal transformation method)	1.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004278	sudden cardiac arrest
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003456	Cryptorchidism	C12.100.500.829.258; C12.200.294.829.258; C12.200.706.258; C12.800.258; C16.131.939.258; C19.391.829.258
D006983	Hypertrichosis	C17.800.329.875
D009069	Movement Disorders	C10.228.662
C566737	Ptosis, Hereditary Congenital 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
bisphenol A	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
kojic acid	increases expression	1
tetrahydropalmatine	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
tamibarotene	decreases expression	1
cylindrospermopsin	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arbutin	increases expression	1
Caffeine	decreases phosphorylation	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases methylation	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT06710574	PHASE4	RECRUITING	Multimodal Image Technologies Investigate the Role and Mechanism of Probiotics in Improving RBD with Parkinson’s Disease
NCT02110745	PHASE4	COMPLETED	The Effect of Induction Technique on Postoperative Pain and Agitation
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT01838278	PHASE3	UNKNOWN	Effectiveness of Vojta Therapy in Motor Development of Preterm Children
NCT04826484	PHASE3	TERMINATED	Opioid Reduction Initiative During Outpatient Pediatric Urologic Procedures Using Exparel
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00001929	PHASE2	COMPLETED	Treatment of Parkinson’s Disease With Eliprodil
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00693472	PHASE2	TERMINATED	Study of Preladenant for the Treatment of Neuroleptic Induced Akathisia (Study P05145)
NCT01385592	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491529	PHASE2	COMPLETED	Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT01491932	PHASE2	COMPLETED	Open-label, Long-term Safety Extension Study of AFQ056 in Parkinson’s Patients With L-dopa Induced Dyskinesias
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT04536987	PHASE2	COMPLETED	Robot Therapy for Rehabilitation of Hand Movement After Stroke
NCT04912115	PHASE2	SUSPENDED	Randomized, Double-Blind, Active Placebo-Controlled Study of Ketamine to Treat Levodopa-Induced Dyskinesia
NCT05636852	PHASE2	TERMINATED	Altropane Dose for Imaging Patients With Suspected Parkinson’s Disease
NCT01701778	PHASE2	COMPLETED	Caudal Versus Intravenous Dexmedetomidine for Supplementation of Caudal Analgesia in Children
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	PHASE2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	PHASE2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty