PLEKHG5

Chr 1AR

pleckstrin homology and RhoGEF domain containing G5

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

NCBI Gene: 57449ENSG00000171680UniProt: O94827OMIM: 611101

The protein activates nuclear factor kappa B (NFKB1) signaling and is located in the cytoplasm. Autosomal recessive mutations cause distal hereditary motor neuronopathy type 4 and recessive intermediate Charcot-Marie-Tooth disease type C through a predicted gain-of-function mechanism.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
MultiplemechanismARLOEUF 0.562 OMIM phenotypes
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
59 unique Pathogenic / Likely Pathogenic· 203 VUS of 499 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
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
1.49Z-score
OE missense 0.84 (0.78–0.90)
552 obs / 659.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.38 (0.26–0.56)
0≤0.351.4
Missense OE0.84 (0.78–0.90)
0≤0.61.4
Synonymous OE1.01
0≤1.21.6
LoF obs/exp: 18 / 47.2Missense obs/exp: 552 / 659.7Syn Z: -0.18
DN
0.6647th %ile
GOF
0.7126th %ile
LOF
0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
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

499 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic16
VUS203
Likely Benign215
Benign13
Conflicting5
43
Pathogenic
16
Likely Pathogenic
203
VUS
215
Likely Benign
13
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
26
1
16
0
43
Likely Pathogenic
15
1
0
0
16
VUS
1
186
14
2
203
Likely Benign
1
2
100
112
215
Benign
1
0
12
0
13
Conflicting
—5
Total44190142114495

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 3 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients