PLEKHG2

Chr 19AR

pleckstrin homology and RhoGEF domain containing G2

Also known as: ARHGEF42, CLG, CTB-60E11.4, LDAMD

NCBI Gene: 64857 ENSG00000090924 UniProt: Q9H7P9 OMIM: 611893

The protein functions as a guanine nucleotide exchange factor that activates CDC42 and RAC1 GTPases, regulating actin polymerization in cellular processes. Biallelic mutations cause autosomal recessive leukodystrophy with acquired microcephaly and variable dystonia. The gene is highly constrained against loss-of-function variants (LOEUF 0.611), consistent with severe clinical consequences when both copies are disrupted.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a RhoGTPase that can activate CDC42 by promoting exchange of GDP for GTP on CDC42. The encoded protein is activated by binding to the beta and gamma subunits of heterotrimeric guanine nucleotide-binding protein. Defects in this gene have been associated with leukodystrophy and acquired microcephaly with or without dystonia. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.611 OMIM phenotype

Clinical Summary— PLEKHG2

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.000

Z-score 3.94

OE 0.44 (0.32–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.80Z-score

OE missense 0.92 (0.86–0.98)

736 obs / 799.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.32–0.61)

0≤0.351.4

Missense OE?0.92 (0.86–0.98)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 25 / 57.2Missense obs/exp: 736 / 799.7Syn Z: 0.89

This gene — mechanism propensity

0.6261th %ile

GOF

0.74top 25%

LOF

0.3550th %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.