ARHGDIA

Chr 17

Rho GDP dissociation inhibitor alpha

Also known as: GDIA1, HEL-S-47e, NPHS8, RHOGDI, RHOGDI-1

NCBI Gene: 396 ENSG00000141522 UniProt: P52565

The protein encoded by this gene controls Rho GTPase homeostasis by inhibiting GDP dissociation and maintaining these signaling molecules in an inactive cytosolic pool. Mutations cause autosomal recessive nephrotic syndrome type 8, affecting kidney function. The gene shows relatively low constraint to loss-of-function mutations (pLI 0.036, LOEUF 0.87).

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that plays a key role in the regulation of signaling through Rho GTPases. The encoded protein inhibits the disassociation of Rho family members from GDP (guanine diphosphate), thereby maintaining these factors in an inactive state. Activity of this protein is important in a variety of cellular processes, and expression of this gene may be altered in tumors. Mutations in this gene have been found in individuals with nephrotic syndrome, type 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.87

Clinical Summary— ARHGDIA

🧬

Gene-Disease Validity (ClinGen)

nephrotic syndrome, type 8 · ARModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 39 VUS of 93 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.036

Z-score 1.86

OE 0.38 (0.19–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.20Z-score

OE missense 0.70 (0.58–0.83)

87 obs / 124.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.19–0.87)

0≤0.351.4

Missense OE?0.70 (0.58–0.83)

0≤0.61.4

Synonymous OE?1.57

0≤1.21.6

LoF obs/exp: 4 / 10.5Missense obs/exp: 87 / 124.9Syn Z: -3.35

This gene — mechanism propensity

0.6162th %ile

GOF

0.5170th %ile

LOF

0.2680th %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

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic1

VUS39

Likely Benign37

Benign3

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	1	0	4
Likely Pathogenic	1	0	0	0	1
VUS	2	37	0	0	39
Likely Benign	1	6	7	23	37
Benign	0	1	2	0	3
Conflicting	—				2
Total	5	46	10	23	86

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap ARHGDIA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →