RAB3GAP2

Chr 1AR

RAB3 GTPase activating non-catalytic protein subunit 2

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

NCBI Gene: 25782 ENSG00000118873 UniProt: Q9H2M9 OMIM: 609275

RAB3GAP2 encodes the regulatory subunit of the Rab3 GTPase-activating complex, which regulates neurotransmitter vesicle trafficking and maintains endoplasmic reticulum structure, with highest expression in brain during neurodevelopment. Biallelic mutations cause Martsolf syndrome and Warburg micro syndrome, both autosomal recessive conditions involving intellectual disability, eye abnormalities, and additional developmental features. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.29), reflecting its critical role in normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.292 OMIM phenotypes

Clinical Summary— RAB3GAP2

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Gene-Disease Validity (ClinGen)

Warburg micro syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

50 unique Pathogenic / Likely Pathogenic· 395 VUS of 883 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RAB3GAP2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

0.87Z-score

OE missense 0.91 (0.85–0.97)

645 obs / 710.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.13–0.29)

0≤0.351.4

Missense OE?0.91 (0.85–0.97)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 16 / 83.6Missense obs/exp: 645 / 710.1Syn Z: 1.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRAB3GAP2-related Martsolf syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.3196th %ile

GOF

0.3094th %ile

LOF

0.75top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

883 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic28

VUS395

Likely Benign298

Benign67

Conflicting34

Pathogenic

Likely Pathogenic

395

VUS

298

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	3	1	0	22
Likely Pathogenic	22	5	1	0	28
VUS	5	332	50	8	395
Likely Benign	0	9	149	140	298
Benign	0	4	61	2	67
Conflicting	—				34
Total	45	353	262	150	844

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap RAB3GAP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →