RAB6A

Chr 11

RAB6A, member RAS oncogene family

Also known as: RAB6

NCBI Gene: 5870 ENSG00000175582 UniProt: P20340 OMIM: 179513

RAB6A encodes a small GTPase that regulates retrograde transport from the Golgi apparatus to the endoplasmic reticulum and recruits VPS13B to Golgi membranes. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants (pLI 0.95, LOEUF 0.34), suggesting intolerance to reduced protein function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the RAB family, which belongs to the small GTPase superfamily. GTPases of the RAB family bind to various effectors to regulate the targeting and fusion of transport carriers to acceptor compartments. This protein is located at the Golgi apparatus, which regulates trafficking in both a retrograde (from early endosomes and Golgi to the endoplasmic reticulum) and an anterograde (from the Golgi to the plasma membrane) directions. Myosin II is an effector of this protein in these processes. This protein is also involved in assembly of human cytomegalovirus (HCMV) by interacting with the cellular protein Bicaudal D1, which interacts with the HCMV virion tegument protein, pp150. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.34

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.952

Z-score 3.22

OE 0.07 (0.02–0.34)

Highly constrained

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

Missense Constraint?

2.50Z-score

OE missense 0.35 (0.27–0.45)

41 obs / 117.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.34)

0≤0.351.4

Missense OE?0.35 (0.27–0.45)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 1 / 14.0Missense obs/exp: 41 / 117.2Syn Z: 0.89

Background carrier burden — how many people carry a rare variant somewhere in RAB6A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 430

162 rare PASS variants

Rare truncating (LoF)

1 in 18,000

25 rare PASS variants

Rare synonymous (reference)

1 in 860

83 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RAB6A. 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 950	1 in 24,000
South Asian	~43k	1 in 660	≈ 1 in 21,000
Remaining (unassigned)	~30k	1 in 1,300	none seen
European (Finnish)	~27k	1 in 1,300	none seen
Admixed American	~22k	1 in 390	≈ 1 in 11,000
African / African American	~21k	1 in 440	none seen
East Asian	~20k	1 in 490	1 in 2,100
Ashkenazi Jewish	~13k	1 in 590	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 580	none seen

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 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓