ARHGAP28

Chr 18

Rho GTPase activating protein 28

NCBI Gene: 79822 ENSG00000088756 UniProt: Q9P2N2 OMIM: 610592

This GTPase activating protein converts Rho-type GTPases to their inactive GDP-bound state, regulating actin cytoskeleton dynamics and cell signaling. The gene shows very low constraint against loss-of-function variants (pLI near zero), but specific pathogenic variants and associated neurological phenotypes have not been established in the provided data. Further clinical and genetic evidence is needed to define disease associations for this gene.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable GTPase activator activity. Predicted to be involved in negative regulation of stress fiber assembly; regulation of actin filament polymerization; and regulation of small GTPase mediated signal transduction. Located in cell junction and nucleoplasm. Implicated in allergic disease. Biomarker of meningioma. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.86

Clinical Summary— ARHGAP28

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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

77 VUS of 95 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.20

OE 0.58 (0.41–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.78Z-score

OE missense 0.87 (0.79–0.97)

266 obs / 304.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.41–0.86)

0≤0.351.4

Missense OE?0.87 (0.79–0.97)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 19 / 32.6Missense obs/exp: 266 / 304.5Syn Z: 0.22

This gene — mechanism propensity

0.6746th %ile

GOF

0.6149th %ile

LOF

0.3259th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

95 submitted variants in ClinVar

ClinVar

Classification Summary

VUS77

Likely Benign7

Benign1

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	77	0	0	77
Likely Benign	4	1	2	7
Benign	1	0	0	1
Total	82	1	2	85

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

View in ClinVar →

108 pathogenic / likely-pathogenic (of 135) ClinVar copy-number / structural variants overlap ARHGAP28 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →