ARHGAP39

Chr 8

Rho GTPase activating protein 39

Also known as: CrGAP, Vilse

NCBI Gene: 80728 ENSG00000147799 UniProt: Q9C0H5 OMIM: 615880

ARHGAP39 encodes a protein with GTPase activator activity that functions in postsynaptic organization at glutamatergic synapses. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and seizures. The gene shows high constraint against loss-of-function variants (LOEUF 0.45), consistent with its essential role in synaptic function.

OMIM ResearchSummary from RefSeq

Predicted to enable GTPase activator activity. Involved in postsynapse organization. Is active in glutamatergic synapse. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.45

Clinical Summary— ARHGAP39

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

186 VUS of 225 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.008

Z-score 4.51

OE 0.28 (0.18–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.52Z-score

OE missense 0.74 (0.69–0.79)

534 obs / 725.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.28 (0.18–0.45)

0≤0.351.4

Missense OE?0.74 (0.69–0.79)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 13 / 46.0Missense obs/exp: 534 / 725.3Syn Z: -0.96

This gene — mechanism propensity

0.6455th %ile

GOF

0.5856th %ile

LOF

0.3744th %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

225 submitted variants in ClinVar

ClinVar

Classification Summary

VUS186

Likely Benign12

Benign2

186

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	186	0	186
Likely Benign	9	3	12
Benign	0	2	2
Total	195	5	200

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 74) ClinVar copy-number / structural variants overlap ARHGAP39 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →