PLEKHG4B

Chr 5

pleckstrin homology and RhoGEF domain containing G4B

Also known as: ARHGEF48

NCBI Gene: 153478 ENSG00000153404 UniProt: Q96PX9 OMIM: 620665

The protein functions as a guanine nucleotide exchange factor that specifically activates CDC42 by exchanging GDP for GTP, regulating actin cytoskeletal remodeling during cell-cell junction formation. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, seizures, and motor abnormalities. The gene shows minimal constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected individuals.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a large protein that contains a pleckstrin homology domain and may function as a guanine nucleotide exchange factor. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.22

Clinical Summary— PLEKHG4B

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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

270 VUS of 332 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.000

Z-score 0.22

OE 0.97 (0.77–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.27Z-score

OE missense 1.03 (0.97–1.09)

762 obs / 741.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.97 (0.77–1.22)

0≤0.351.4

Missense OE?1.03 (0.97–1.09)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 50 / 51.7Missense obs/exp: 762 / 741.3Syn Z: -0.60

This gene — mechanism propensity

0.5280th %ile

GOF

0.7028th %ile

LOF

0.48top 25%

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

332 submitted variants in ClinVar

ClinVar

Classification Summary

VUS270

Likely Benign31

Benign7

270

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	270	0	0	270
Likely Benign	29	0	2	31
Benign	2	3	2	7
Total	301	3	4	308

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

View in ClinVar →

132 pathogenic / likely-pathogenic (of 183) ClinVar copy-number / structural variants overlap PLEKHG4B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →