PLEKHG5

Chr 1AR

pleckstrin homology and RhoGEF domain containing G5

Also known as: ARHGEF45, CMTRIC, DSMA4, GEF720, HMNR4, Syx, Tech

NCBI Gene: 57449ENSG00000171680UniProt: O94827

This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, recessive intermediate CMIM #615376
AR
Neuronopathy, distal hereditary motor, autosomal recessive 4MIM #611067
AR
595
ClinVar variants
57
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— PLEKHG5
🧬
Gene-Disease Validity (ClinGen)
neuromuscular disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 204 VUS of 595 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.56LOEUF
pLI 0.000
Z-score 3.94
OE 0.38 (0.26–0.56)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.49Z-score
OE missense 0.84 (0.78–0.90)
552 obs / 659.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.26–0.56)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.78–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 18 / 47.2Missense obs/exp: 552 / 659.7Syn Z: -0.18

ClinVar Variant Classifications

595 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic20
VUS204
Likely Benign320
Benign6
Conflicting8
37
Pathogenic
20
Likely Pathogenic
204
VUS
320
Likely Benign
6
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
1
18
0
37
Likely Pathogenic
15
0
5
0
20
VUS
0
172
31
1
204
Likely Benign
1
3
150
166
320
Benign
0
0
6
0
6
Conflicting
—8
Total34176210167595

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

View in ClinVar →

Protein Context — Lollipop Plot

PLEKHG5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Charcot-Marie-Tooth disease, recessive intermediate C

MIM #615376

Molecular basis of disorder known

Autosomal recessive

Neuronopathy, distal hereditary motor, autosomal recessive 4

MIM #611067

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
PLEKHG5 regulates autophagy, survival and MGMT expression in U251-MG glioblastoma cells.
Witte KE et al.·Sci Rep
2020
Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies.
Chen Z et al.·Eur J Neurol
2021
Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease.
Villar-Quiles RN et al.·Neuromuscul Disord
2021
PLEKHG5-related autosomal recessive lower motor neuron disease with dysmyelination in peripheral nerves.
Miao Y et al.·Clin Neuropathol
2021
Genetic predisposition to differentiated thyroid cancer in the Polish population.
Borowczyk M et al.·Pol Arch Intern Med
2024
Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease.
Kim HJ et al.·Orphanet J Rare Dis
2013
Genetic Modifiers of Hereditary Neuromuscular Disorders and Cardiomyopathy.
Bazrafshan S et al.·Cells
2021
The RhoGEF protein Plekhg5 self-associates via its PH domain to regulate apical cell constriction.
Popov IK et al.·Mol Biol Cell
2024
Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: A case report.
Beijer D et al.·J Neuromuscul Dis
2022Case report
The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset.
Maystadt I et al.·Am J Hum Genet
2007
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Cannabis UseAdolescent

TECH App Marijuana Use Intervention for Court-Involved Adolescents

ACTIVE NOT RECRUITING
NCT05979272Phase NANorthwestern UniversityStarted 2023-06-21
Treatment as usualTeen Empowerment through Computerized Health (TECH) app

External Resources

Links to major genomics databases and tools