NM_001025616.3:c.473A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001025616.3(ARHGAP24):c.473A>G(p.Gln158Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,946 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 2 hom. )

Consequence

ARHGAP24
NM_001025616.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.29

Publications

10 publications found

Variant links:

Genes affected

ARHGAP24 (HGNC:25361): (Rho GTPase activating protein 24) This gene encodes a Rho-GTPase activating protein, which is specific for the small GTPase family member Rac. Binding of the encoded protein by filamin A targets it to sites of membrane protrusion, where it antognizes Rac. This results in suppression of lamellae formation and promotion of retraction to regulate cell polarity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ARHGAP24 Gene-Disease associations (from GenCC):

familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARHGAP24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04208663).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3 link	c.473A>G	p.Gln158Arg	missense_variant	Exon 5 of 10	ENST00000395184.6	NP_001020787.2	Q8N264-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6 link	c.473A>G	p.Gln158Arg	missense_variant	Exon 5 of 10	2	NM_001025616.3	ENSP00000378611.1		Q8N264-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000446

AC:

112

AN:

251158

AF XY:

0.000354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00284

AC:

127

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.000393

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000683

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 26, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with steroid-resistant nephrotic syndrome (SRNS) and/or focal segmental glomerulosclerosis (FSGS) in published literature (PMID: 21911940, 30406062); Published functional studies demonstrate a damaging effect as the p.(Q158R) reduces enzymatic acitivty (PMID: 21911940); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36168627, 21911940, 30406062) -

Mar 14, 2016

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 158 of the ARHGAP24 protein (p.Gln158Arg). This variant is present in population databases (rs112475438, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ARHGAP24-related conditions (PMID: 21911940, 30406062). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224509). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects ARHGAP24 function (PMID: 21911940). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

ARHGAP24-related disorder

Uncertain:1

Jan 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ARHGAP24 c.473A>G variant is predicted to result in the amino acid substitution p.Gln158Arg. This variant was reported in the heterozygous state to segregate with end-stage kidney disease and focal segmental glomerulosclerosis in a family with three affected and two unaffected individuals, and functional assays demonstrated reduced ARHGAP24 enzymatic activity (Akilesh et al. 2011. PubMed ID: 21911940). This variant was also reported in the heterozygous state in two unrelated individuals with steroid-resistant nephrotic syndrome (Table S2, Varner et al. 2018. PubMed ID: 30406062). This variant is reported in 0.32% of alleles in individuals of Latino descent in gnomAD, including one homozygous individual. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

T;.;.;.;.;T;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.042

T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.40

N;N;.;.;.;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

N;D;D;N;D;N;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0090

D;T;T;D;T;D;D

Sift4G

Uncertain

0.027

D;T;T;D;T;D;D

Polyphen

1.0

D;D;.;D;.;.;P

Vest4

0.93

MutPred

0.58

Gain of MoRF binding (P = 0.0346);Gain of MoRF binding (P = 0.0346);.;.;.;.;.;

MVP

0.62

MPC

0.22

ClinPred

0.14

GERP RS

6.0

Varity_R

0.48

gMVP

0.74

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over