RAB3B

Chr 1

RAB3B, member RAS oncogene family

NCBI Gene: 5865 ENSG00000169213 UniProt: P20337 OMIM: 179510

RAB3B encodes a small GTPase that regulates synaptic vesicle trafficking and fusion at nerve terminals, particularly in dopaminergic synapses. Mutations cause autosomal recessive Cortical dysplasia, complex, with other brain malformations 8, characterized by complex brain malformations and developmental abnormalities. This gene follows autosomal recessive inheritance and affects critical neurodevelopmental processes during brain formation.

OMIM ResearchSummary from RefSeq, UniProt

Enables GDP binding activity; GTPase activity; and myosin V binding activity. Involved in several processes, including positive regulation of dopamine uptake involved in synaptic transmission; regulation of synaptic vesicle cycle; and regulation of vesicle size. Located in perinuclear region of cytoplasm and vesicle. Is active in dopaminergic synapse and synaptic vesicle membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.75

Clinical Summary— RAB3B

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

24 VUS of 26 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.315

Z-score 2.04

OE 0.24 (0.10–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.94Z-score

OE missense 0.77 (0.66–0.91)

104 obs / 134.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.10–0.75)

0≤0.351.4

Missense OE?0.77 (0.66–0.91)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 2 / 8.4Missense obs/exp: 104 / 134.9Syn Z: 0.81

This gene — mechanism propensity

0.82top 10%

GOF

0.75top 25%

LOF

0.2776th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

26 submitted variants in ClinVar

ClinVar

Classification Summary

VUS24

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	24	24
Likely Benign	0	0
Benign	0	0
Total	24	24

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap RAB3B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →