RAB7A

Chr 3AD

RAB7A, member RAS oncogene family

Also known as: CMT2B, PRO2706, RAB7

NCBI Gene: 7879 ENSG00000075785 UniProt: P51149 OMIM: 602298

The RAB7A protein is a small GTPase that regulates vesicular trafficking in late endosomes and endosome-to-lysosome transport, playing essential roles in neurotrophin signaling and axonal transport. Mutations cause Charcot-Marie-Tooth disease type 2B, an autosomal dominant peripheral neuropathy. This gene is highly constrained against loss-of-function variation, reflecting its critical cellular functions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

RAB family members are small, RAS-related GTP-binding proteins that are important regulators of vesicular transport. Each RAB protein targets multiple proteins that act in exocytic / endocytic pathways. This gene encodes a RAB family member that regulates vesicle traffic in the late endosomes and also from late endosomes to lysosomes. This encoded protein is also involved in the cellular vacuolation of the VacA cytotoxin of Helicobacter pylori. Mutations at highly conserved amino acid residues in this gene have caused some forms of Charcot-Marie-Tooth (CMT) type 2 neuropathies. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.281 OMIM phenotype

Clinical Summary— RAB7A

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease type 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 83 VUS of 214 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RAB7A

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?

0.28LOEUF

pLI 0.969

Z-score 3.04

OE 0.00 (0.00–0.28)

Highly constrained

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

Missense Constraint?

2.28Z-score

OE missense 0.40 (0.32–0.51)

46 obs / 114.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.28)

0≤0.351.4

Missense OE?0.40 (0.32–0.51)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 0 / 10.8Missense obs/exp: 46 / 114.7Syn Z: 0.30

This gene — mechanism propensity

0.6549th %ile

GOF

0.6540th %ile

LOF

0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, loss-of-function and gain-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 · 1 literature citation

LOFLOEUF 0.28

GOFprediction 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.

Literature Evidence

DNFurthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29130394 ↗

ClinVar Variant Classifications

214 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS83

Likely Benign86

Benign24

Conflicting10

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	0	0	0	0
VUS	4	44	35	0	83
Likely Benign	0	1	51	34	86
Benign	0	0	23	1	24
Conflicting	—				10
Total	4	49	109	35	207

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap RAB7A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →