RAB3GAP2

protein-coding

RAB3 GTPase activating non-catalytic protein subunit 2, the group of Small nucleolar RNA protein coding host genes|MicroRNA protein coding host genes

Gene summary

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.[provided by RefSeq, Oct 2009]

MANE transcript

NM_012414.4

Inheritance

ClinVar variants

P:53U:368B:179

Top phenotype

Warburg micro syndrome 2; Martsolf syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr1:220,148,293-220,272,529

External References & Databases

Ensembl (ENSG00000118873)

Transcript & Mutation Effects

hg38 • Region Span ~124.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RAB18 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700247

Submitter: Ambry Genetics

Warburg micro syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013641

Submitter: Labcorp Genetics (formerly Invitae)

cataract-intellectual disability-hypogonadism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008929

Submitter: Orphanet

autosomal recessive spastic paraplegia type 69SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018421

Submitter: Orphanet

Warburg micro syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: Orphanet

Warburg micro syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013641

Submitter: PanelApp Australia

Martsolf syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:8000008

Submitter: G2P

Warburg micro syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: ClinGen

RAB3GAP2 was first reported in relation to autosomal recessive Martsolf Syndrome in 2006 (Aligianis et al. PMID 16532399) and autosomal recessive Warburg Micro syndrome in 2011 (Borck et al. PMID 20967465). Martsolf syndrome and Warburg Micro syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, microcephaly, hypotonia and neurodevelopmental delay, in which Martsolf syndrome presents with a milder and Warburg Micro syndrome presents with a more severe clinical phenotype. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions. Therefore, the following disease entities: Martsolf syndrome 1 (OMIM: 212720) and Warburg micro syndrome 2 (OMIM: 614225) have been lumped into one disease entity in this curation. Eighteen variants (4 missense, 1 in-frame indel, 10 nonsense, 2 frameshift, 1 splice site) that have been reported in 8 Martsolf and 10 Warburg Micro probands in 5 publications (PMIDs: 16532399, 20967465, 23420520, 32740904, 32376645) are included in this curation; the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by biochemical function assays (PMIDs 24891604). In summary, RAB3GAP2 is definitively associated with autosomal recessive Warburg micro spectrum, a disease entity that includes both Martsolf syndrome (OMIM: 212720) and Warburg micro syndrome (OMIM: 614225). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the Brain Malformations GCEP on November 28, 2023.

Clinical Genomic Database (CGD)

Warburg micro syndrome 2; Martsolf syndrome 1AR

Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Endocrine; Ophthalmologic; Pharmacogenomic

Rationale: The condition can include a risk of glaucoma, and early treatment may be beneficial; Medical care related to endocrine manifestations may be indicated; Agents that may contribute to glaucoma should be avoided

Refs: 677168; 16532399; 20967465

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAB3GAP2 variants in ClinVar

16 Conditions Cataloged

Warburg micro syndrome 2Total: 501

Martsolf syndromeTotal: 482

not providedTotal: 174

Inborn genetic diseasesTotal: 163

not specifiedTotal: 59

RAB3GAP2-related disorderTotal: 40

Martsolf syndrome 1Total: 23

MicrocephalyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012414.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	152 clinvar	1 clinvar	163
missense	1 clinvar	4 clinvar	340 clinvar	23 clinvar	3 clinvar	371
nonsense	7 clinvar	8 clinvar	2 clinvar			17
start loss			1 clinvar			1
frameshift	9 clinvar	10 clinvar	2 clinvar			21
splice donor/acceptor (+/-2bp)	2 clinvar	12 clinvar	13 clinvar			27
Total	19	34	368	175	4	600

Highest pathogenic variant AF is 0.000011153397

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012414.4	RefSeq	NP_036546.2	35	MANE Select
ENST00000358951.7	Ensembl	ENSP00000351832.2	35	MANE Select
ENST00000474178.1	Ensembl	ENSP00000420156.1	4	Standard
ENST00000685286.1	Ensembl	ENSP00000509457.1	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Effects of Botulinum toxin
Rab regulation of trafficking
COPI-independent Golgi-to-ER retrograde traffic

Biological Process

intracellular protein transport
regulation of GTPase activity
positive regulation of GTPase activity
establishment of protein localization to endoplasmic reticulum membrane
positive regulation of protein lipidation

Molecular Function

GTPase activator activity
protein binding
enzyme activator activity
Rab guanyl-nucleotide exchange factor activity
Rab GTPase binding

Cellular Component

endoplasmic reticulum membrane
cytosol
plasma membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358951
Coding exons: 35
Length: 124162
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.868	645	710	0.908	0.0000352	9119
Missense (PolyPhen)		158	222.27	0.71086		2812
Synonymous	1.05	238	259	0.917	0.0000134	2637
Loss of Function	6.85	16	83.6	0.191	0.00000426	987

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00012	0.000087	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00016	0.00016	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulatory subunit of a GTPase activating protein that has specificity for Rab3 subfamily (RAB3A, RAB3B, RAB3C and RAB3D). Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones. Rab3 GTPase-activating complex specifically converts active Rab3-GTP to the inactive form Rab3- GDP. Required for normal eye and brain development. May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non- synaptic vesicular release of neurotransmitters. {ECO:0000269|PubMed:9733780}.;
Disease: DISEASE: 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 mental retardation, spastic diplegia, and hypogonadism. {ECO:0000269|PubMed:20967465}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.420
RVIS EVS: -1.08
RVIS percentile EVS: 7.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.919

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium