RAB3A

Chr 19AD

RAB3A, member RAS oncogene family

Also known as: SCA52

NCBI Gene: 5864 ENSG00000105649 UniProt: P20336 OMIM: 179490

RAB3A encodes a small GTPase that controls regulated exocytosis and secretion by recruiting, tethering and docking secretory vesicles to the plasma membrane in neurons and other cell types. Mutations cause spinocerebellar ataxia 52 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI = 0.95, LOEUF = 0.32), reflecting its essential role in vesicle trafficking.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables GTPase activity and myosin V binding activity. Involved in several processes, including acrosomal vesicle exocytosis; plasma membrane repair; and regulation of plasma membrane repair. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.321 OMIM phenotype

Clinical Summary— RAB3A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 17 VUS of 32 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.946

Z-score 2.82

OE 0.00 (0.00–0.32)

Highly constrained

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

Missense Constraint?

2.32Z-score

OE missense 0.47 (0.39–0.57)

71 obs / 151.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.32)

0≤0.351.4

Missense OE?0.47 (0.39–0.57)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 0 / 9.2Missense obs/exp: 71 / 151.5Syn Z: 0.62

This gene — mechanism propensity

0.7133th %ile

GOF

0.6932th %ile

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.32

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

32 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS17

Likely Benign3

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	2
Likely Pathogenic	1	0	0	1
VUS	17	0	0	17
Likely Benign	0	2	1	3
Benign	0	0	1	1
Total	18	4	2	24

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap RAB3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →