RAB3GAP2

Chr 1

RAB3 GTPase activating non-catalytic protein subunit 2

Also known as: MARTS1, RAB3-GAP150, RAB3GAP150, SPG69, WARBM2, p150

NCBI Gene: 25782ENSG00000118873UniProt: Q9H2M9

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]

Primary Disease Associations & Inheritance

UniProtMartsolf syndrome 1
UniProtWarburg micro syndrome 2
480
ClinVar variants
28
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RAB3GAP2
🧬
Gene-Disease Validity (ClinGen)
Warburg micro syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 240 VUS of 480 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.29LOEUF
pLI 0.987
Z-score 6.85
OE 0.19 (0.13–0.29)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.87Z-score
OE missense 0.91 (0.85–0.97)
645 obs / 710.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.13–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.85–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 16 / 83.6Missense obs/exp: 645 / 710.1Syn Z: 1.05

ClinVar Variant Classifications

480 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic12
VUS240
Likely Benign158
Benign50
Conflicting4
16
Pathogenic
12
Likely Pathogenic
240
VUS
158
Likely Benign
50
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
14
0
16
Likely Pathogenic
6
1
5
0
12
VUS
2
227
8
3
240
Likely Benign
0
5
72
81
158
Benign
0
3
45
2
50
Conflicting
—4
Total923714486480

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RAB3GAP2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RAB3GAP2-related Martsolf syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — RAB3GAP2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.
Deneubourg C et al.·Autophagy
2022
Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome.
Xu W et al.·Cold Spring Harb Mol Case Stud
2020Review
A new missense variant in RAB3GAP2 in a family with muscular dystrophy-short stature and defective autophagy: An expansion of the micro/Martsolf spectrum or a new phenotype?
Mora-Roldan GA et al.·Am J Med Genet A
2022Case report
Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome.
Handley MT et al.·Hum Mutat
2013
The Warburg Micro Syndrome-associated Rab3GAP-Rab18 module promotes autolysosome maturation through the Vps34 Complex I.
Takáts S et al.·FEBS J
2021
Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights.
Abdel-Hamid MS et al.·Clin Genet
2020Review
Three Iranian patients with rare subtypes of hereditary spastic paraplegia (HSP): SPG76, SPG56, and SPG69.
Sadr Z et al.·Neurogenetics
2024Cohort
RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio.
Ström K et al.·Cell Rep
2026
A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome.
Borck G et al.·Hum Genet
2011Case report
Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome.
Aligianis IA et al.·Am J Hum Genet
2006
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools