RALGAPA1

protein-coding

Ral GTPase activating protein catalytic subunit alpha 1

Gene summary

This gene encodes a major subunit of the RAL-GTPase activating protein. A similar protein in mouse binds E12, a transcriptional regulator of immunoglobulin genes. The mouse protein also functions in skeletal muscle by binding to the regulatory 14-3-3 proteins upon stimulation with insulin or muscle contraction. A pseudogene of this gene has been identified on chromosome 9. [provided by RefSeq, Oct 2016]

Previous symbols:

GARNL1

MANE transcript

NM_001346249.2

Inheritance

AR, AD

ClinVar variants

P:14U:251B:56

Top phenotype

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr14:35,538,352-35,809,304

External References & Databases

Ensembl (ENSG00000174373)

Transcript & Mutation Effects

hg38 • Region Span ~271.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032921

Submitter: PanelApp Australia

neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032921

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032921

Submitter: G2P

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032921

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Pulmonary

Intervention: Pulmonary

Rationale: Among other findings, individuals have been described with neonatal respiratory insufficiency requiring intervention, and awareness may allow such interventions to be performed efficiently

Refs: 32004447

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RALGAPA1 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 197

not providedTotal: 82

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationTotal: 28

not specifiedTotal: 26

RALGAPA1-related disorderTotal: 14

Long QT syndromeTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001346249.2. 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			2 clinvar	40 clinvar	1 clinvar	43
missense	1 clinvar		243 clinvar	13 clinvar	2 clinvar	259
nonsense	4 clinvar	2 clinvar	2 clinvar			8
start loss						0
frameshift	3 clinvar	3 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	8	6	251	53	3	321

Highest pathogenic variant AF is 0.000003246163

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001346249.2	RefSeq	NP_001333178.1	41	MANE Select
ENST00000680220.1	Ensembl	ENSP00000506280.1	41	MANE Select
NM_001283043.3	RefSeq	NP_001269972.1	41	Standard
NM_001283044.3	RefSeq	NP_001269973.1	41	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ralgapa1	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

ralgapa1

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrated Breast Cancer Pathway

Biological Process

regulation of small GTPase mediated signal transduction
activation of GTPase activity

Molecular Function

GTPase activator activity
protein heterodimerization activity

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307138
Coding exons: 40
Length: 270953
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.53	716	1.04e+3	0.692	0.0000518	13697
Missense (PolyPhen)		327	551.23	0.59322		7324
Synonymous	0.767	330	348	0.948	0.0000174	3922
Loss of Function	8.03	16	105	0.153	0.00000583	1297

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000082	0.000079	rare
South Asian	0.000067	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic subunit of the heterodimeric RalGAP1 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB. {ECO:0000250}.;

Recessive Scores

pRec: 0.129

Intolerance Scores

LoFtool: 0.0300
RVIS EVS: -1.21
RVIS percentile EVS: 5.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.969

Gene Damage Prediction

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