RAB27A

Chr 15AR

RAB27A, member RAS oncogene family

Also known as: GS2, HsT18676, RAB27, RAM

NCBI Gene: 5873 ENSG00000069974 UniProt: P51159 OMIM: 603868

RAB27A encodes a small GTPase that regulates vesicle trafficking in the late endocytic pathway and controls cytotoxic granule exocytosis in immune cells. Mutations cause Griscelli syndrome type 2, an autosomal recessive disorder characterized by partial albinism and severe immunodeficiency due to impaired lymphocyte function. The gene shows low constraint against loss-of-function variants (high LOEUF score), consistent with the recessive inheritance pattern where both alleles must be affected to cause disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in protein transport and small GTPase mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Griscelli syndrome, type 2MIM #607624

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Griscelli syndrome type 2 · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

140

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.65

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.65LOEUF

pLI 0.000

Z-score 0.01

OE 1.00 (0.61–1.65)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.51Z-score

OE missense 1.13 (0.98–1.31)

135 obs / 119.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.00 (0.61–1.65)

0≤0.351.4

Missense OE?1.13 (0.98–1.31)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 10 / 10.0Missense obs/exp: 135 / 119.2Syn Z: 0.77

Background carrier burden — how many people carry a rare variant somewhere in RAB27A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

303 rare PASS variants

Rare truncating (LoF)

1 in 2,000

49 rare PASS variants

Rare synonymous (reference)

1 in 560

94 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RAB27A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 150	1 in 1,900
South Asian	~43k	1 in 210	1 in 2,400
Remaining (unassigned)	~30k	1 in 120	1 in 2,500
European (Finnish)	~27k	1 in 1,200	≈ 1 in 27,000
Admixed American	~22k	1 in 150	1 in 1,300
African / African American	~21k	1 in 220	≈ 1 in 21,000
East Asian	~20k	1 in 300	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 870	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 160	≈ 1 in 950

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓