ARHGAP35

Chr 19

Rho GTPase activating protein 35

Also known as: GRF-1, GRLF1, P190-A, P190A, p190ARhoGAP, p190RhoGAP

NCBI Gene: 2909 ENSG00000160007 UniProt: Q9NRY4 OMIM: 605277

The protein functions as a Rho GTPase-activating protein that regulates cell adhesion, migration, and morphogenesis, playing critical roles in retinal development, neural tube fusion, cerebral hemisphere midline fusion, and axon outgrowth and guidance. Mutations cause neurodevelopmental disorders with intellectual disability, developmental delay, and structural brain abnormalities, inherited in an autosomal dominant pattern. The gene is extremely intolerant to loss-of-function variants, indicating that proper protein dosage is critical for normal neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

The human glucocorticoid receptor DNA binding factor, which associates with the promoter region of the glucocorticoid receptor gene (hGR gene), is a repressor of glucocorticoid receptor transcription. The amino acid sequence deduced from the cDNA sequences show the presence of three sequence motifs characteristic of a zinc finger and one motif suggestive of a leucine zipper in which 1 cysteine is found instead of all leucines. The GRLF1 enhances the homologous down-regulation of wild-type hGR gene expression. Biochemical analysis suggests that GRLF1 interaction is sequence specific and that transcriptional efficacy of GRLF1 is regulated through its interaction with specific sequence motif. The level of expression is regulated by glucocorticoids. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.06

Clinical Summary— ARHGAP35

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 130 VUS of 173 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 6.68

OE 0.00 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.16Z-score

OE missense 0.60 (0.56–0.64)

510 obs / 852.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.60 (0.56–0.64)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 52.0Missense obs/exp: 510 / 852.0Syn Z: 0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveARHGAP35-related developmental disorderLOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.3689th %ile

LOF

0.77top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 100% of P/LP variants are LoF · LOEUF 0.06

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

173 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic9

VUS130

Likely Benign6

Benign3

Conflicting2

Pathogenic

Likely Pathogenic

130

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	0	0	0	11
Likely Pathogenic	9	0	0	0	9
VUS	1	129	0	0	130
Likely Benign	0	6	0	0	6
Benign	0	0	0	3	3
Conflicting	—				2
Total	21	135	0	3	161

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap ARHGAP35 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →