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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
PLEKHG5
pleckstrin homology and RhoGEF domain containing G5
Chromosome 1 Β· 1p36.31
NCBI Gene: 57449Ensembl: ENSG00000171680.23HGNC: HGNC:29105UniProt: A0A804EMX3
33PubMed Papers
22Diseases
0Drugs
87Pathogenic Variants
RESEARCH IMPACT
Variant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
positive regulation of canonical NF-kappaB signal transductionangiogenesisendothelial cell chemotaxisendothelial cell migrationneuronopathy, distal hereditary motor, autosomal recessive 4Charcot-Marie-Tooth disease recessive intermediate CAutosomal recessive intermediate Charcot-Marie-Tooth disease type Cgenetic disorder
✦AI Summary

PLEKHG5 is a guanine exchange factor (GEF) that primarily functions as an activator of the small GTPase RAB26, playing critical roles in neuronal and non-neuronal tissues. In motoneurons, PLEKHG5 regulates unconventional secretion of SOD1 through secretory autophagy, wherein it facilitates the fusion of autophagosomes with secretory lysosomal-related organelles and subsequent exocytosis 1. PLEKHG5 also controls autophagy more broadly and activates NF-ΞΊB signaling 2, with reported involvement in neuronal cell differentiation [UniProt reference]. Beyond the nervous system, PLEKHG5 regulates endothelial cell chemotaxis and migration during angiogenesis, and affects macrophage and osteoclast function [UniProt reference]. Mutations in PLEKHG5 cause autosomal recessive intermediate Charcot-Marie-Tooth disease (RI-CMT) 34, characterized by axonal neuropathy with distal motor and sensory involvement and abnormal myelin formation 5. PLEKHG5 mutations also cause distal hereditary motor neuron disease (dHMN4) 1. In the context of SOD1-linked ALS, reduced PLEKHG5 expression impairs mutant SOD1 secretion 1. Additionally, PLEKHG5 expression correlates with glioblastoma grade and patient survival, with elevated expression promoting tumor migration and invasion 6. Outside cancer, PLEKHG5 participates in autophagy regulation in endometriosis pathogenesis 7.

Sources cited
1
PLEKHG5 drives unconventional secretion of SOD1 via secretory autophagy through RAB26 activation; PLEKHG5 deletion causes SOD1 accumulation at presynaptic sites and relates to motoneuron disease
PMID: 39366938
2
PLEKHG5 is associated with autosomal recessive intermediate Charcot-Marie-Tooth disease
PMID: 25326399
3
PLEKHG5 mutations cause autosomal recessive intermediate CMT with axonal neuropathy; mutant proteins show defects in NF-ΞΊB activation
PMID: 23844677
4
PLEKHG5 mutations in lower motor neuron disease show dysmyelination and myelin abnormalities on nerve biopsy
PMID: 34236308
5
PLEKHG5 regulates RAB26-mediated autophagy and NF-ΞΊB signaling; affects MGMT expression and glioblastoma cell survival
PMID: 33318498
6
PLEKHG5 expression correlates with glioma grade and prognosis; promotes glioma migration and invasion
PMID: 31309383
7
PLEKHG5 participates in autophagy regulation in endometriosis through interaction with RND3
PMID: 41137701
Disease Associationsβ“˜22
neuronopathy, distal hereditary motor, autosomal recessive 4Open Targets
0.77Strong
Charcot-Marie-Tooth disease recessive intermediate COpen Targets
0.69Moderate
Autosomal recessive intermediate Charcot-Marie-Tooth disease type COpen Targets
0.64Moderate
genetic disorderOpen Targets
0.50Moderate
juvenile amyotrophic lateral sclerosisOpen Targets
0.41Moderate
neuromuscular diseaseOpen Targets
0.37Weak
neurodegenerative diseaseOpen Targets
0.37Weak
Charcot-Marie-Tooth diseaseOpen Targets
0.35Weak
spinal muscular atrophy, facioscapulohumeral typeOpen Targets
0.33Weak
Varicose veinsOpen Targets
0.32Weak
hereditary spastic paraplegiaOpen Targets
0.26Weak
glomerulonephritisOpen Targets
0.24Weak
distal hereditary motor neuropathyOpen Targets
0.17Weak
Testicular atrophyOpen Targets
0.12Weak
acquired thrombocytopeniaOpen Targets
0.12Weak
Genetic motor neuron diseaseOpen Targets
0.11Weak
hereditary motor neuron diseaseOpen Targets
0.11Weak
peripheral neuropathyOpen Targets
0.11Weak
hepatocellular carcinomaOpen Targets
0.07Suggestive
amyotrophic lateral sclerosisOpen Targets
0.06Suggestive
Charcot-Marie-Tooth disease, recessive intermediate CUniProt
Neuronopathy, distal hereditary motor, autosomal recessive 4UniProt
Pathogenic Variants87
NM_020631.6(PLEKHG5):c.2542C>T (p.Arg848Ter)Pathogenic
Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4|not provided|Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2026β†’ Residue 848
NM_020631.6(PLEKHG5):c.2366_2367del (p.Leu789fs)Pathogenic
Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4|not provided
β˜…β˜…β˜†β˜†2026β†’ Residue 789
NM_020631.6(PLEKHG5):c.2269G>T (p.Glu757Ter)Pathogenic
Inborn genetic diseases|Autosomal recessive PLEKHG5-related disorders|Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜…β˜†β˜†2025β†’ Residue 757
NM_020631.6(PLEKHG5):c.2053C>T (p.Gln685Ter)Pathogenic
not provided|Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C|Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2025β†’ Residue 685
NM_020631.6(PLEKHG5):c.1289C>A (p.Ser430Ter)Pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C|PLEKHG5-related disorder|Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2024β†’ Residue 430
NM_020631.6(PLEKHG5):c.2149G>T (p.Glu717Ter)Pathogenic
Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2024β†’ Residue 717
NM_020631.6(PLEKHG5):c.1327G>T (p.Glu443Ter)Pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C|Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜…β˜†β˜†2024β†’ Residue 443
NM_020631.6(PLEKHG5):c.2902del (p.Val968fs)Pathogenic
Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2024β†’ Residue 968
NM_020631.6(PLEKHG5):c.2788C>T (p.Arg930Ter)Pathogenic
Inborn genetic diseases|Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2023β†’ Residue 930
NM_020631.6(PLEKHG5):c.985-2A>GPathogenic
not provided|Charcot-Marie-Tooth disease recessive intermediate C|Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C|Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2022
NM_020631.6(PLEKHG5):c.1132-2A>CPathogenic
Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜…β˜†β˜†2022
NM_020631.6(PLEKHG5):c.1738G>T (p.Glu580Ter)Pathogenic
not provided|Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜…β˜†β˜†2021β†’ Residue 580
NM_020631.6(PLEKHG5):c.2062C>T (p.Gln688Ter)Pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜†β˜†β˜†2026β†’ Residue 688
NM_020631.6(PLEKHG5):c.1800+1G>ALikely pathogenic
Glioma susceptibility 1|Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜†β˜†β˜†2026
NM_020631.6(PLEKHG5):c.2628dup (p.Lys877Ter)Pathogenic
Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜†β˜†β˜†2026β†’ Residue 877
NM_020631.6(PLEKHG5):c.1778_1784del (p.Met593fs)Pathogenic
Charcot-Marie-Tooth disease recessive intermediate C;Neuronopathy, distal hereditary motor, autosomal recessive 4
β˜…β˜†β˜†β˜†2025β†’ Residue 593
NM_020631.6(PLEKHG5):c.185del (p.Lys62fs)Pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜†β˜†β˜†2025β†’ Residue 62
NM_020631.6(PLEKHG5):c.2540del (p.Pro847fs)Pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜†β˜†β˜†2025β†’ Residue 847
NM_020631.6(PLEKHG5):c.302+1G>TLikely pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜†β˜†β˜†2025
NM_020631.6(PLEKHG5):c.2158G>T (p.Glu720Ter)Pathogenic
Neuronopathy, distal hereditary motor, autosomal recessive 4;Charcot-Marie-Tooth disease recessive intermediate C
β˜…β˜†β˜†β˜†2025β†’ Residue 720
View on ClinVar β†—
Related Genes
RND3Protein interaction95%RHOAProtein interaction91%RND1Protein interaction79%STARD13Shared pathway22%C18orf32Shared pathway20%S100A7AShared pathway20%
Tissue Expression6 tissues
Heart
100%
Brain
63%
Ovary
61%
Lung
33%
Liver
19%
Bone Marrow
16%
Gene Interaction Network
Click a node to explore
PLEKHG5RND3RHOARND1STARD13C18orf32S100A7A
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt O94827
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.71LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.56 [0.45–0.71]
RankingsWhere PLEKHG5 stands among ~20K protein-coding genes
  • #11,388of 20,598
    Most Researched33
  • #866of 5,498
    Most Pathogenic Variants87 Β· top quartile
  • #5,398of 17,882
    Most Constrained (LOEUF)0.71
Genes detectedPLEKHG5
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.
PMID: 34602496
J Neuromuscul Dis Β· 2022
1.00
2
Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.
PMID: 39366938
Nat Commun Β· 2024
0.90
3
Intermediate Charcot-Marie-Tooth disease.
PMID: 25326399
Neurosci Bull Β· 2014
0.80
4
PLEKHG5: Merging phenotypes and disease mechanisms in Charcot-Marie-Tooth neuropathy and lower motor neuron disease.
PMID: 33492783
Eur J Neurol Β· 2021
0.70
5
RND3 Inhibits Endometriosis Progression by Regulating Autophagy and Oxidative Stress Through PLEKHG5.
PMID: 41137701
FASEB J Β· 2025
0.60