PLEKHG5

Chr 1AR

pleckstrin homology and RhoGEF domain containing G5

ENSG00000171680 UniProt: O94827 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons (By similarity). Involved in the control of neuronal cell differentiation (PubMed:11704860). Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. Also affects the migration, adhesion, and matrix/bone degradation in macrophages and osteoclasts (PubMed:23777631)

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.562 OMIM phenotypes

Clinical Summary— PLEKHG5

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Gene-Disease Validity (ClinGen)

neuromuscular disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

90 unique Pathogenic / Likely Pathogenic· 590 VUS of 1528 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ncbi: SyntaxError: Bad control character in string literal in JSON at position 94 (line 1 column 95)

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 OE?0.38 (0.26–0.56)

0≤0.351.4

Missense OE?0.84 (0.78–0.90)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 18 / 47.2Missense obs/exp: 552 / 659.7Syn Z: -0.18

This gene — mechanism propensity

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

1528 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53

Likely Pathogenic37

VUS590

Likely Benign689

Benign89

Conflicting66

Pathogenic

Likely Pathogenic

590

VUS

689

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	50	1	2	0	53
Likely Pathogenic	34	3	0	0	37
VUS	4	524	57	5	590
Likely Benign	1	19	305	364	689
Benign	2	12	70	5	89
Conflicting	—				66
Total	91	559	434	374	1,524

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap PLEKHG5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →