ARHGAP29

protein-coding

Rho GTPase activating protein 29, the group of AH/BAR family Rho GTPase activating proteins

Gene summary

Rap1 is a small GTPase that, through effectors, regulates Rho GTPase signaling. These effectors- Rasip1, Radil, and the protein encoded by this gene- translocate to the cell membrane, where they form a multiprotein complex. This complex is necessary for Rap1-induced inhibition of Rho signaling. Defects in this gene may be a cause of nonsyndromic cleft lip with or without cleft palate. [provided by RefSeq, Jun 2016]

MANE transcript

NM_004815.4

Inheritance

ClinVar variants

P:10U:179B:39

Top phenotype

cleft lip with or without cleft palate

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr1:94,148,988-94,275,068

External References & Databases

Ensembl (ENSG00000137962)

Transcript & Mutation Effects

hg38 • Region Span ~126.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cleft lip with or without cleft palateDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016034

Submitter: Illumina

ARHGAP29-related non-syndromic orofacial cleftDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1060132

Submitter: ClinGen

*ARHGAP29* was first reported in relation to autosomal dominant non-syndromic orofacial cleft in 2012 (Leslie et al., PMID: 23008150). Eleven variants (five nonsense/frameshift, 4 canonical splice site, 1 inframe deletion, 1 missense, that have been reported in 11 probands in five publications (PMIDs: 25704602, 25512736, 32698641, 27350171, 28029220) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function with reduced penetrance observed in family pedigrees. This gene-disease relationship is also supported by expression in relevant tissues and in patients, protein interaction with IRF6, and a mouse model with oral adhesions (PMIDs: 28029220, 32698641, 23008150, 28817352). In summary, there is definitive evidence supporting the relationship between *ARHGAP29* and autosomal dominant non-syndromic orofacial cleft. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date August 15, 2024 (SOP Version 10).

orofacial cleftSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0000358

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGAP29 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 144

not providedTotal: 43

ARHGAP29-related disorderTotal: 36

not specifiedTotal: 29

Nonsyndromic cleft lip with or without cleft palateTotal: 4

Isolated cleft palateTotal: 1

Cleft palateTotal: 1

Non-syndromic orofacial cleftTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004815.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				24 clinvar	1 clinvar	25
missense	1 clinvar		175 clinvar	11 clinvar	2 clinvar	189
nonsense	2 clinvar		2 clinvar			4
start loss				1 clinvar		1
frameshift	1 clinvar	2 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	1 clinvar			5
Total	7	3	179	36	3	228

Highest pathogenic variant AF is 0.00001611234

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004815.4	RefSeq	NP_004806.3	22	MANE Select
ENST00000260526.11	Ensembl	ENSP00000260526.6	22	MANE Select
NM_001328664.2	RefSeq	NP_001315593.1	22	Standard
NM_001328665.2	RefSeq	NP_001315594.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hypothetical Craniofacial Development Pathway
Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases

Biological Process

Rho protein signal transduction
positive regulation of GTPase activity
regulation of small GTPase mediated signal transduction

Molecular Function

GTPase activator activity
PDZ domain binding
metal ion binding

Cellular Component

cytoplasm
cytosol
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260526
Coding exons: 22
Length: 126081
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125747
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.21	559	646	0.866	0.0000325	8323
Missense (PolyPhen)		169	250.48	0.6747		3382
Synonymous	0.758	206	220	0.935	0.0000108	2345
Loss of Function	6.09	8	58.1	0.138	0.00000317	748

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has strong activity toward RHOA, and weaker activity toward RAC1 and CDC42. May act as a specific effector of RAP2A to regulate Rho. In concert with RASIP1, suppresses RhoA signaling and dampens ROCK and MYH9 activities in endothelial cells and plays an essential role in blood vessel tubulogenesis. {ECO:0000269|PubMed:15752761, ECO:0000269|PubMed:9305890}.;

Recessive Scores

pRec: 0.0887

Intolerance Scores

LoFtool: 0.481
RVIS EVS: -1.48
RVIS percentile EVS: 3.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.431

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium