RAB3GAP2

Summary

RAB3GAP2 (RAB3 GTPase activating non-catalytic protein subunit 2, HGNC:17168) is a protein-coding gene on chromosome 1q41, encoding Rab3 GTPase-activating protein non-catalytic subunit (Q9H2M9). Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.

The protein encoded by this gene belongs to the RAB3 protein family, members of which are involved in regulated exocytosis of neurotransmitters and hormones. This protein forms the Rab3 GTPase-activating complex with RAB3GAP1, where it constitutes the regulatory subunit, whereas the latter functions as the catalytic subunit. This gene has the highest level of expression in the brain, consistent with it having a key role in neurodevelopment. Mutations in this gene are associated with Martsolf syndrome.

Source: NCBI Gene 25782 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Warburg micro syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 883 total — 23 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 139
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_012414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17168
Approved symbol	RAB3GAP2
Name	RAB3 GTPase activating non-catalytic protein subunit 2
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	RAB3-GAP150, KIAA0839, DKFZP434D245, SPG69
Ensembl gene	ENSG00000118873
Ensembl biotype	protein_coding
OMIM	609275
Entrez	25782

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 21 protein_coding, 13 retained_intron, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000237724, ENST00000358951, ENST00000462353, ENST00000474178, ENST00000474966, ENST00000475769, ENST00000478976, ENST00000484658, ENST00000491005, ENST00000491305, ENST00000684982, ENST00000685286, ENST00000685664, ENST00000686381, ENST00000687065, ENST00000687394, ENST00000687647, ENST00000688035, ENST00000688281, ENST00000688904, ENST00000689820, ENST00000690315, ENST00000690373, ENST00000690379, ENST00000690824, ENST00000691661, ENST00000691862, ENST00000692208, ENST00000692813, ENST00000692972, ENST00000693454, ENST00000693602, ENST00000888367, ENST00000888368, ENST00000888369, ENST00000888370, ENST00000888371, ENST00000888372, ENST00000888373, ENST00000947881, ENST00000947882

RefSeq mRNA: 1 — MANE Select: NM_012414 NM_012414

CCDS: CCDS31028

Canonical transcript exons

ENST00000358951 — 35 exons

Exon	Start	End
ENSE00000801825	220153968	220154057
ENSE00000801826	220157270	220157488
ENSE00000801827	220157802	220157876
ENSE00000801828	220159386	220159421
ENSE00000801829	220162198	220162268
ENSE00000801830	220164733	220164799
ENSE00000801831	220167293	220167399
ENSE00000801832	220167502	220167675
ENSE00000801833	220170892	220171120
ENSE00000801834	220171889	220172049
ENSE00000801835	220172637	220172742
ENSE00000801838	220184036	220184163
ENSE00000801839	220185651	220185741
ENSE00000801842	220190377	220190520
ENSE00000801843	220191068	220191284
ENSE00000801844	220193240	220193379
ENSE00000801846	220195298	220195377
ENSE00000801847	220196250	220196398
ENSE00001407270	220272223	220272453
ENSE00001427382	220148293	220151406
ENSE00001442994	220195078	220195167
ENSE00001504943	220182257	220182354
ENSE00001504944	220182718	220182931
ENSE00003479565	220213856	220213979
ENSE00003485748	220153185	220153406
ENSE00003495168	220210801	220210876
ENSE00003496695	220232799	220232863
ENSE00003510536	220151606	220151764
ENSE00003512538	220189703	220189767
ENSE00003531111	220205907	220206006
ENSE00003532027	220190064	220190146
ENSE00003546521	220212887	220212968
ENSE00003654709	220210388	220210489
ENSE00003665276	220210955	220211002
ENSE00003787441	220202276	220202374

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 96.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.0785 / max 66.4794, expressed in 1097 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17553	21.1933	1817
17551	2.0785	1097
17554	1.8669	1011
17552	0.3841	170

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	96.94	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.83	gold quality
dorsal root ganglion	UBERON:0000044	96.29	gold quality
pericardium	UBERON:0002407	96.07	gold quality
trigeminal ganglion	UBERON:0001675	95.97	gold quality
pons	UBERON:0000988	95.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.66	gold quality
cardia of stomach	UBERON:0001162	95.61	gold quality
type B pancreatic cell	CL:0000169	95.60	gold quality
endothelial cell	CL:0000115	95.58	gold quality
superior vestibular nucleus	UBERON:0007227	95.34	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.30	gold quality
mammary duct	UBERON:0001765	95.28	gold quality
nipple	UBERON:0002030	95.19	gold quality
postcentral gyrus	UBERON:0002581	95.19	gold quality
secondary oocyte	CL:0000655	95.18	gold quality
parietal lobe	UBERON:0001872	95.13	gold quality
epithelium of mammary gland	UBERON:0003244	95.05	gold quality
superior surface of tongue	UBERON:0007371	94.94	gold quality
substantia nigra pars compacta	UBERON:0001965	94.89	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.76	gold quality
subthalamic nucleus	UBERON:0001906	94.69	gold quality
inferior vagus X ganglion	UBERON:0005363	94.38	gold quality
ventral tegmental area	UBERON:0002691	94.28	gold quality
oocyte	CL:0000023	94.13	gold quality
pylorus	UBERON:0001166	93.98	gold quality
lateral globus pallidus	UBERON:0002476	93.94	gold quality
tongue	UBERON:0001723	93.87	gold quality
corpus callosum	UBERON:0002336	93.80	gold quality
body of tongue	UBERON:0011876	93.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

134 targeting RAB3GAP2, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-10401-5P	99.99	65.79	948
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-8068	99.98	73.85	2376
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7D-5P	99.96	71.76	1632

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 13)

• Data show that at chemical synapses, Rab3 performs specific functions in synpatic vesicle exocytosis. (PMID:18485483)
• KIF1Bbeta- and KIF1A-mediated axonal transport of presynaptic regulator RAB3GAP2 occurs in a GTP-dependent manner through MADD. (PMID:18849981)
• functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype (PMID:20967465)
• 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)
• Rab18 and a Rab18 GEF complex of Rab3GAP1 and Rab3GAP2 have roles in the endoplasmic reticulum structure (PMID:24891604)
• RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy (PMID:25495476)
• 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)
• Mutation in RAB3GAP2 gene is associated with Warburg micro syndrome and Martsolf syndrome. (PMID:29419336)
• The Warburg Micro Syndrome-associated Rab3GAP-Rab18 module promotes autolysosome maturation through the Vps34 Complex I. (PMID:32248620)
• Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome. (PMID:32376645)
• Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights. (PMID:32740904)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab3gap2	ENSDARG00000044136
mus_musculus	Rab3gap2	ENSMUSG00000039318
rattus_norvegicus	Rab3gap2	ENSRNOG00000002353
drosophila_melanogaster	Rab3-GAP	FBGN0027505
caenorhabditis_elegans	rbg-2	WBGENE00004318

Protein

Protein identifiers

Rab3 GTPase-activating protein non-catalytic subunit — Q9H2M9 (reviewed: Q9H2M9)

Alternative names: RGAP-iso, Rab3 GTPase-activating protein 150 kDa subunit, Rab3-GAP p150, Rab3-GAP regulatory subunit

All UniProt accessions (12): Q9H2M9, A0A8I5KRK1, A0A8I5KRP1, A0A8I5KSQ5, A0A8I5KUS2, A0A8I5KWJ9, A0A8I5KY07, A0A8I5KYQ0, A0A8I5KZB3, A0A8I5QJC9, A0A8I5QJG4, F8WDJ2

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins. The complex has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and has guanine nucleotide exchange factor (GEF) activity towards RAB18. The Rab3GAP complex acts as a GEF for RAB18 by 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 human 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 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.

Tissue specificity. Ubiquitous.

Disease relevance. Martsolf syndrome 1 (MARTS1) [MIM:212720] An autosomal recessive disease characterized by congenital cataracts, intellectual disability, and hypogonadism. The disease is caused by variants affecting the gene represented in this entry. Warburg micro syndrome 2 (WARBM2) [MIM:614225] 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.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H2M9-1	1	yes
Q9H2M9-2	2

RefSeq proteins (1): NP_036546* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026059	Rab3GAP2	Family
IPR029257	RAB3GAP2_C	Domain
IPR032839	RAB3GAP_N	Domain

Pfam: PF14655, PF14656

UniProt features (16 total): sequence variant 5, modified residue 5, splice variant 2, chain 1, region of interest 1, sequence conflict 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-Q9H2M9-F1	79.77	0.40

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 (5): 39, 450, 901, 916, 978

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: 521 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_GTPASE_ACTIVITY, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_MACROAUTOPHAGY

GO Biological Process (8): intracellular protein transport (GO:0006886), macroautophagy (GO:0016236), regulation of GTPase activity (GO:0043087), establishment of protein localization to endoplasmic reticulum membrane (GO:0097051), synaptic signaling (GO:0099536), positive regulation of protein lipidation (GO:1903061), positive regulation of endoplasmic reticulum tubular network organization (GO:1903373), positive regulation of autophagosome assembly (GO:2000786)

GO Molecular Function (6): GTPase activator activity (GO:0005096), enzyme activator activity (GO:0008047), enzyme regulator activity (GO:0030234), small GTPase binding (GO:0031267), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (8): autophagosome (GO:0005776), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), protein-containing complex (GO:0032991), presynaptic membrane (GO:0042734), 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
autophagosome assembly	2
GTPase activity	2
GTPase regulator activity	2
catalytic activity	2
cytoplasm	2
cellular anatomical structure	2
intracellular protein localization	1
protein transport	1
intracellular transport	1
autophagy	1
regulation of hydrolase activity	1
establishment of protein localization to endoplasmic reticulum	1
establishment of protein localization to membrane	1
cell-cell signaling	1
synapse	1
protein lipidation	1
positive regulation of protein modification process	1
positive regulation of lipoprotein metabolic process	1
regulation of protein lipidation	1
positive regulation of organelle organization	1
endoplasmic reticulum tubular network organization	1
regulation of endoplasmic reticulum tubular network organization	1
positive regulation of macroautophagy	1
positive regulation of vacuole organization	1
positive regulation of organelle assembly	1
regulation of autophagosome assembly	1
enzyme activator activity	1
enzyme regulator activity	1
molecular function activator activity	1
molecular function regulator activity	1
GTPase binding	1
GTP binding	1
GDP binding	1
binding	1
vacuole	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1518 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB3GAP2	RAB3GAP1	Q15042	997
RAB3GAP2	DMXL2	Q8TDJ6	900
RAB3GAP2	RAB18	Q9NP72	868
RAB3GAP2	MADD	Q8WXG6	853
RAB3GAP2	WDR7	Q9Y4E6	832
RAB3GAP2	TBC1D20	Q96BZ9	815
RAB3GAP2	RAB3A	P20336	784
RAB3GAP2	RASA1	P20936	705
RAB3GAP2	REEP2	Q9BRK0	687
RAB3GAP2	DMXL1	Q9Y485	649
RAB3GAP2	TECPR2	O15040	605
RAB3GAP2	REEP1	Q9H902	566
RAB3GAP2	ARL6IP1	Q15041	537
RAB3GAP2	SCOC	Q9UIL1	527
RAB3GAP2	SPG11	Q96JI7	510

IntAct

91 interactions, top by confidence:

A	B	Type	Score
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
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
VAPA	FAM83G	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
FANCD2OS	CNOT1	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
RAB3GAP2	RRBP1	psi-mi:“MI:0915”(physical association)	0.400
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
SIRT2	DEGS1	psi-mi:“MI:0914”(association)	0.350
MOSPD2	FLNA	psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
MAP1LC3A		psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
COPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPE	ESYT2	psi-mi:“MI:0914”(association)	0.350
VAPA	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (185): RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS), RAB3GAP1 (Co-fractionation), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-RNA), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Proximity Label-MS), RAB3GAP2 (Synthetic Lethality), RAB3GAP2 (Proximity Label-MS), RAB3GAP2 (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IC37, A1A4K3, A2CEI4, B1WC10, E9PY46, F1QEB7, F4IDS7, O08658, O13046, O75694, O75717, O95876, P33194, P37199, P59328, Q08D69, Q10569, Q10570, Q16531, Q32NR9, Q3U1J4, Q4ADV7, Q566H4, Q5DQR4, Q5R649, Q5U1Z0, Q5ZLG9, Q6P6Z0, Q6PGF3, Q6PJI9, Q7XWP1, Q802U2, Q805F9, Q8BMG7, Q8C0M0, Q8C456, Q8CEC0, Q8CJF7, Q8K1X1, Q8NFP9

Diamond homologs: Q5U1Z0, Q8BMG7, Q9H2M9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	12.3×	3e-03
SARS-CoV-1-host interactions	5	11.7×	7e-03
SARS-CoV-1 Infection	6	11.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	25
Uncertain significance	394
Likely benign	285
Benign	67

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100788	NM_012414.4(RAB3GAP2):c.1434G>A (p.Trp478Ter)	Pathogenic
100789	NM_012414.4(RAB3GAP2):c.3637C>T (p.Arg1213Ter)	Pathogenic
100790	NM_012414.4(RAB3GAP2):c.3085G>T (p.Glu1029Ter)	Pathogenic
1030256	NM_012414.4(RAB3GAP2):c.2366_2370delinsGACTGTGG (p.Gln789_Ser790delinsArgLeuTrp)	Pathogenic
1173050	NM_012414.4(RAB3GAP2):c.2488C>T (p.Gln830Ter)	Pathogenic
1173051	NM_012414.4(RAB3GAP2):c.1955T>A (p.Leu652Ter)	Pathogenic
1319794	NM_012414.4(RAB3GAP2):c.3862G>T (p.Glu1288Ter)	Pathogenic
1435827	NM_012414.4(RAB3GAP2):c.1998+1G>A	Pathogenic
1820	NM_012414.4(RAB3GAP2):c.3154G>T (p.Gly1052Cys)	Pathogenic
2193003	NM_012414.4(RAB3GAP2):c.694C>T (p.Arg232Ter)	Pathogenic
2415504	NM_012414.4(RAB3GAP2):c.1348dup (p.Ser450fs)	Pathogenic
2425802	NC_000001.10:g.(?220330592)(220335630_?)del	Pathogenic
2628350	NM_012414.4(RAB3GAP2):c.2366_2370delinsGACTGTGGTTTT (p.Gln789fs)	Pathogenic
2921941	NM_012414.4(RAB3GAP2):c.340del (p.Met114fs)	Pathogenic
2952637	NM_012414.4(RAB3GAP2):c.3613del (p.Met1205fs)	Pathogenic
30782	NM_012414.4(RAB3GAP2):c.499_507del (p.Phe167_Thr169del)	Pathogenic
423205	NM_012414.4(RAB3GAP2):c.2844dup (p.Gln949fs)	Pathogenic
436479	NM_012414.4(RAB3GAP2):c.2207dup (p.Leu737fs)	Pathogenic
504367	NM_012414.4(RAB3GAP2):c.165_168del (p.Glu56fs)	Pathogenic
521623	NM_012414.4(RAB3GAP2):c.2213-1G>A	Pathogenic
687736	GRCh37/hg19 1q41(chr1:220408340-220490046)x1	Pathogenic
988329	NM_012414.4(RAB3GAP2):c.1743_1746del (p.Leu581fs)	Pathogenic
988570	NM_012414.4(RAB3GAP2):c.214del (p.Thr72fs)	Pathogenic
1208853	NM_012414.4(RAB3GAP2):c.2786dup (p.Leu930fs)	Likely pathogenic
1319793	NM_012414.4(RAB3GAP2):c.434+1G>A	Likely pathogenic
1319795	NM_012414.4(RAB3GAP2):c.1966del (p.Asp656fs)	Likely pathogenic
1723391	NM_012414.4(RAB3GAP2):c.2095C>T (p.Arg699Ter)	Likely pathogenic
2412696	NM_012414.4(RAB3GAP2):c.2287_2291del (p.Ala762_Gly763insTer)	Likely pathogenic
2412697	NM_012414.4(RAB3GAP2):c.1201del (p.Ala400_Val401insTer)	Likely pathogenic
2431759	NM_012414.4(RAB3GAP2):c.1040+1G>T	Likely pathogenic

SpliceAI

5061 predictions. Top by Δscore:

Variant	Effect	Δscore
1:220153408:T:C	acceptor_gain	1.0000
1:220153408:T:TC	acceptor_gain	1.0000
1:220153414:A:AC	acceptor_gain	1.0000
1:220153963:TTTAC:T	donor_loss	1.0000
1:220153964:TTA:T	donor_loss	1.0000
1:220153965:TA:T	donor_loss	1.0000
1:220153966:A:C	donor_loss	1.0000
1:220153967:CCTGT:C	donor_loss	1.0000
1:220154054:TTCCC:T	acceptor_loss	1.0000
1:220154055:TCCC:T	acceptor_loss	1.0000
1:220154056:CC:C	acceptor_gain	1.0000
1:220154056:CCCTA:C	acceptor_loss	1.0000
1:220154057:CC:C	acceptor_gain	1.0000
1:220154057:CCTAA:C	acceptor_loss	1.0000
1:220154058:CTAA:C	acceptor_loss	1.0000
1:220154352:T:TA	donor_gain	1.0000
1:220157266:TTACC:T	donor_loss	1.0000
1:220157267:TAC:T	donor_loss	1.0000
1:220157268:A:AC	donor_gain	1.0000
1:220157269:C:CA	donor_loss	1.0000
1:220157269:C:CC	donor_gain	1.0000
1:220157269:CCTT:C	donor_gain	1.0000
1:220157269:CCTTA:C	donor_gain	1.0000
1:220157485:CTGC:C	acceptor_gain	1.0000
1:220157798:TTACC:T	donor_loss	1.0000
1:220157800:A:T	donor_loss	1.0000
1:220157800:ACCT:A	donor_gain	1.0000
1:220157801:C:T	donor_loss	1.0000
1:220157801:CCTC:C	donor_gain	1.0000
1:220157803:T:TA	donor_gain	1.0000

AlphaMissense

9158 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:220193242:T:A	K423I	1.000
1:220193246:A:G	W422R	1.000
1:220193246:A:T	W422R	1.000
1:220195301:G:T	A346D	1.000
1:220195325:A:T	L338H	1.000
1:220195334:G:T	A335E	1.000
1:220195337:A:T	V334D	1.000
1:220210854:A:G	W153R	1.000
1:220210854:A:T	W153R	1.000
1:220162251:A:G	W1058R	0.999
1:220162251:A:T	W1058R	0.999
1:220167310:A:G	W1024R	0.999
1:220167310:A:T	W1024R	0.999
1:220191100:T:A	R485S	0.999
1:220191100:T:G	R485S	0.999
1:220191123:A:G	W478R	0.999
1:220191123:A:T	W478R	0.999
1:220191261:A:G	W432R	0.999
1:220191261:A:T	W432R	0.999
1:220191278:C:G	R426P	0.999
1:220191279:G:T	R426S	0.999
1:220191284:C:T	G424E	0.999
1:220193241:T:A	K423N	0.999
1:220193241:T:G	K423N	0.999
1:220193251:C:G	R420P	0.999
1:220193289:T:A	R407S	0.999
1:220193289:T:G	R407S	0.999
1:220193357:G:T	R385S	0.999
1:220195325:A:G	L338P	0.999
1:220195335:C:G	A335P	0.999

dbSNP variants (sampled 300 via entrez): RS1000039753 (1:220215260 G>A), RS1000045881 (1:220246029 G>A), RS1000058765 (1:220219372 A>G), RS1000073987 (1:220215580 T>C), RS1000152188 (1:220185318 G>A,C), RS1000244616 (1:220229953 T>C), RS1000269639 (1:220152936 C>A), RS1000275265 (1:220270119 G>T), RS1000286349 (1:220175448 A>G), RS1000294242 (1:220247853 A>G), RS1000306950 (1:220257967 A>C,G), RS1000417397 (1:220264332 G>A,C), RS1000463161 (1:220208588 T>C), RS1000467492 (1:220264037 A>G), RS1000503907 (1:220167932 C>T)

Disease associations

OMIM: gene MIM:609275 | disease phenotypes: MIM:614225, MIM:212720, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
RAB18 deficiency	Definitive	Autosomal recessive
Martsolf syndrome 1	Definitive	Autosomal recessive
Warburg micro syndrome 2	Strong	Autosomal recessive
cataract-intellectual disability-hypogonadism syndrome	Supportive	Autosomal recessive
Warburg micro syndrome	Supportive	Autosomal recessive
autosomal recessive spastic paraplegia type 69	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 2 (MONDO:0013641), Martsolf syndrome (MONDO:0023910), Martsolf syndrome 1 (MONDO:8000008), microcephaly (MONDO:0001149), microphthalmia (MONDO:0021129), amenorrhea (MONDO:0001836), esophageal atresia/tracheoesophageal fistula (MONDO:0008586), RAB18 deficiency (MONDO:0700247), (MONDO:0008929), Warburg micro syndrome (MONDO:0016649), autosomal recessive spastic paraplegia type 69 (MONDO:0018421)

Orphanet (3): Cataract-intellectual disability-hypogonadism syndrome (Orphanet:1387), Micro syndrome (Orphanet:2510), Esophageal atresia (Orphanet:1199)

HPO phenotypes

139 total (30 of 139 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000126	Hydronephrosis
HP:0000218	High palate
HP:0000221	Furrowed tongue
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002337_71	Amyotrophic lateral sclerosis (sporadic)	9.000000e-06
GCST003985_21	Breast size	8.000000e-07
GCST012282_3	BMI x environmental factors (excluding physical activity) interaction	5.000000e-07

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006527	smoking status measurement
EFO:0009374	energy intake measurement
EFO:0009695	household income
EFO:0010810	protein intake measurement
EFO:0010811	carbohydrate intake measurement
EFO:0011015	educational attainment

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D008850	Microphthalmos	C11.250.566; C16.131.384.666
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)
C536028	Martsolf syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	decreases expression, decreases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
decabromobiphenyl ether	decreases expression	1
2-butenal	decreases expression	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

62 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
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
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
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT03748732	Not specified	UNKNOWN	Extensive Circumferential Partial Thickness Sclerectomy in Nanophthalmic Eyes
NCT04759560	Not specified	UNKNOWN	Biometric Characteristics of the Eye With Microcornea/Microphthalmia and Congenital Cataract Before And After Cataract Extraction
NCT05954403	Not specified	RECRUITING	National Cohort on Congenital Defects of the Eye
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women
NCT00556400	PHASE1/PHASE2	TERMINATED	Treatment of Menorrhagia in Women With Thrombocytopenia Using Platelets or Platelets and Hormones
NCT01187043	PHASE1/PHASE2	COMPLETED	Determination of the Lowest, Safe and Effective Dose of Proellex
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00011388	Not specified	COMPLETED	Reproductive Effects of Pesticide, PCB and Mercury Exposure in Laotian Immigrants