RAB32

Chr 6AD

RAB32, member RAS oncogene family

Also known as: PARK26

NCBI Gene: 10981 ENSG00000118508 UniProt: Q13637 OMIM: 612906

This small GTPase regulates intracellular membrane trafficking, anchors protein kinase A to mitochondria, and controls mitochondrial fission, phagosome maturation, and melanosome biogenesis. Mutations cause autosomal dominant Parkinson disease 26, with the gene showing low constraint to loss-of-function variants (pLI 0.0006, LOEUF 1.29). The protein also stimulates LRRK2-mediated phosphorylation of RAB10, linking it to other Parkinson disease pathways.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene anchors the type II regulatory subunit of protein kinase A to the mitochondrion and aids in mitochondrial fission. The encoded protein also appears to be involved in autophagy and melanosome secretion. Variations in this gene may be linked to leprosy. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.291 OMIM phenotype

Clinical Summary— RAB32

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.29LOEUF

pLI 0.001

Z-score 0.96

OE 0.66 (0.36–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.26Z-score

OE missense 1.06 (0.92–1.23)

132 obs / 124.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.66 (0.36–1.29)

0≤0.351.4

Missense OE?1.06 (0.92–1.23)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 6 / 9.1Missense obs/exp: 132 / 124.0Syn Z: -0.60

This gene — mechanism propensity

0.80top 10%

GOF

0.76top 25%

LOF

0.2385th %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.