RAB5C

Chr 17

RAB5C, member RAS oncogene family

Also known as: L1880, RAB5CL, RAB5L, RABL

NCBI Gene: 5878 ENSG00000108774 UniProt: P51148 OMIM: 604037

RAB5C encodes a small GTPase that regulates early endocytic trafficking by cycling between inactive and active forms to recruit effectors responsible for vesicle formation, movement, and fusion with target membranes. The gene is highly constrained against loss-of-function variants (pLI 0.94, LOEUF 0.36), suggesting mutations would likely cause severe developmental phenotypes, though specific associated diseases have not yet been established in the literature.

OMIM ResearchSummary from RefSeq, UniProt

Members of the Rab protein family are small GTPases of the Ras superfamily that are thought to ensure fidelity in the process of docking and/or fusion of vesicles with their correct acceptor compartment (Han et al., 1996 [PubMed 8646882]).[supplied by OMIM, Nov 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.36

Clinical Summary— RAB5C

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 26 VUS of 44 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.36LOEUF

pLI 0.937

Z-score 3.11

OE 0.08 (0.03–0.36)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.42Z-score

OE missense 0.67 (0.57–0.79)

98 obs / 146.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.36)

0≤0.351.4

Missense OE?0.67 (0.57–0.79)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 1 / 13.2Missense obs/exp: 98 / 146.2Syn Z: 0.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateRAB5C-related neurodevelopmental disorderDNAD

This gene — mechanism propensity

0.6840th %ile

GOF

0.5955th %ile

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-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

LOFLOEUF 0.36

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

44 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS26

Benign1

Conflicting1

Likely Pathogenic

VUS

Benign

Conflicting

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	1	0	0	1
VUS	3	23	0	0	26
Likely Benign	0	0	0	0	0
Benign	0	0	0	1	1
Conflicting	—				1
Total	3	24	0	1	29

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 7) ClinVar copy-number / structural variants overlap RAB5C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →