RAB18

Chr 10AR

RAB18, member RAS oncogene family

Also known as: RAB18LI1, WARBM3

NCBI Gene: 22931 ENSG00000099246 UniProt: Q9NP72 OMIM: 602207

RAB18 encodes a small GTPase that regulates intracellular membrane trafficking, maintains endoplasmic reticulum structure, and is required for endoplasmic reticulum-lipid droplet contacts. Mutations cause Warburg micro syndrome type 3, an autosomal recessive disorder affecting eye and brain development. The gene is highly constrained against loss-of-function variants (pLI 0.91, LOEUF 0.39), consistent with its essential role in neurological development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of a family of Ras-related small GTPases that regulate membrane trafficking in organelles and transport vesicles. Knockdown studies is zebrafish suggest that this protein may have a role in eye and brain development. Mutations in this gene are associated with Warburg micro syndrome type 3. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.391 OMIM phenotype

Clinical Summary— RAB18

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Gene-Disease Validity (ClinGen)

Warburg micro syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 105 VUS of 210 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RAB18

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.39LOEUF

pLI 0.910

Z-score 2.96

OE 0.08 (0.03–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.39Z-score

OE missense 0.63 (0.51–0.77)

68 obs / 108.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.39)

0≤0.351.4

Missense OE?0.63 (0.51–0.77)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 1 / 12.2Missense obs/exp: 68 / 108.8Syn Z: -0.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRAB18-related Warburg micro syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6260th %ile

GOF

0.6931th %ile

LOF

0.4825th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

210 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic4

VUS105

Likely Benign39

Benign37

Conflicting4

Pathogenic

Likely Pathogenic

105

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	3	1	0	6
Likely Pathogenic	2	1	1	0	4
VUS	3	34	67	1	105
Likely Benign	0	3	23	13	39
Benign	0	1	36	0	37
Conflicting	—				4
Total	7	42	128	14	195

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap RAB18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →