RABL3

Chr 3AD

RAB, member of RAS oncogene family like 3

Also known as: PNCA5

NCBI Gene: 285282 ENSG00000144840 UniProt: Q5HYI8 OMIM: 618542

RABL3 encodes a small GTPase that regulates KRAS prenylation, modulates cell proliferation, and is essential for ciliogenesis by promoting ciliary vesicle formation at the mother centriole. The gene is not highly constrained against loss-of-function variants, and no Mendelian diseases have been definitively associated with RABL3 mutations in humans. While implicated in pancreatic cancer and required for lymphocyte development in model systems, pathogenic variants causing pediatric neurological disorders have not been established.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable GTP binding activity; GTPase activity; and protein homodimerization activity. Involved in regulation of Ras protein signal transduction and regulation of protein lipidation. Predicted to be active in endomembrane system. Implicated in pancreatic cancer. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.971 OMIM phenotype

Clinical Summary— RABL3

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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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ClinVar Variants

21 VUS of 51 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.001

Z-score 1.65

OE 0.52 (0.29–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.43Z-score

OE missense 0.89 (0.77–1.04)

115 obs / 128.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.29–0.97)

0≤0.351.4

Missense OE?0.89 (0.77–1.04)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 7 / 13.5Missense obs/exp: 115 / 128.8Syn Z: -0.13

This gene — mechanism propensity

0.6162th %ile

GOF

0.6346th %ile

LOF

0.3939th %ile

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports dominant-negative as the primary mechanism.

DNprediction 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.

ClinVar Variant Classifications

51 submitted variants in ClinVar

ClinVar

Classification Summary

VUS21

Likely Benign10

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	20	0	0	21
Likely Benign	0	2	2	6	10
Benign	0	0	2	0	2
Total	1	22	4	6	33

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap RABL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →