RALA
protein-codingRAS like proto-oncogene A, the group of RAS type GTPase family
Gene summary
The product of this gene belongs to the small GTPase superfamily, Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors. This gene encodes a low molecular mass ras-like GTP-binding protein that shares about 50% similarity with other ras proteins. [provided by RefSeq, Jul 2008]
- RAL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~84.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859142
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859142
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0859142
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*RALA* encodes a small Ras-like GTPase. *RALA* was first reported in relation to autosomal dominant complex neurodevelopmental disorder (also known as Hiatt-Neu-Cooper neurodevelopmental disorder) in 2018 (Hiatt et al., PMID: 30500825). The main phenotypic features include intellectual disability, speech problems, autism spectrum disorder, hypotonia, structural brain abnormalities, seizures, dysmorphic features, skeletal anomalies, delayed growth, and macrocephaly. Seven *de novo* variants (six missense and one inframe) reported in 13 individuals are included in this curation (PMIDs: 30500825, 30761613, 33875846, 35846790). All the variants are located in the GTP/GDP-binding region of RALA. Two variants are recurrent, p.Val25Met and p.Lys128Arg. Functional studies showed that four missense variants exhibited loss of function, while two resulted in gain of function (PMIDs: 30500825, 35846790). One of the missense variants leading to gain of function is a brain somatic variant identified in a child with epilepsy and focal cortical dysplasia type II (PMID: 35846790). This gene-disease relationship is also supported by experimental evidence. Biallelic loss-of-function variants in *RALGAPA1*, encoding the catalytic subunit of the RalGAP complex that regulates RALA activity, cause a neurodevelopmental disorder with features overlapping those caused by *RALA* variants and lead to a constitutive activation of RALA in patient cells (PMID: 32004447). Additionally, *in utero* electroporation of the *RALA* c.G482A somatic variant (identified in an individual with focal cortical dysplasia) in the embryonic mouse brain induced abnormal cortical neuron migration (PMID: 35846790). In summary, there is definitive evidence supporting the relationship between *RALA* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 3, 2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RALA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005402.4. 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 | 1 | 32 | 1 | 34 | ||
| missense | 5 | 8 | 41 | 4 | 4 | 62 |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 5 | 9 | 49 | 36 | 5 | 104 |
Highest pathogenic variant AF is 6.8408065e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005393.2 | 4 | MANE Select | |
| Ensembl | ENSP00000005257.2 | 4 | MANE Select | |
| Ensembl | ENSP00000413227.1 | 4 | Standard | |
| Ensembl | ENSP00000388975.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Rap1 signaling pathway - Homo sapiens (human)
- Ras signaling pathway - Homo sapiens (human)
- Phospholipase D signaling pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Pancreatic cancer - Homo sapiens (human)
Biological Process
- neural tube closure
- exocytosis
- chemotaxis
- cell cycle
- signal transduction
Molecular Function
- GTPase activity
- protein binding
- GTP binding
- myosin binding
- GDP binding
Cellular Component
- plasma membrane
- focal adhesion
- cell surface
- endocytic vesicle
- cytoplasmic vesicle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000005257
- Coding exons
- 4
- Length
- 84642
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.70 | 29 | 108 | 0.268 | 0.00000535 | 1362 |
| Missense (PolyPhen) | 5 | 53.335 | 0.093747 | 650 | ||
| Synonymous | 1.00 | 32 | 40.1 | 0.799 | 0.00000223 | 370 |
| Loss of Function | 3.09 | 0 | 11.1 | 0.00 | 7.16e-7 | 122 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling (PubMed:20005108). Key regulator of LPAR1 signaling and competes with GRK2 for binding to LPAR1 thus affecting the signaling properties of the receptor. Required for anchorage- independent proliferation of transformed cells (PubMed:19306925). During mitosis, supports the stabilization and elongation of the intracellular bridge between dividing cells. Cooperates with EXOC2 to recruit other components of the exocyst to the early midbody (PubMed:18756269). {ECO:0000269|PubMed:18756269, ECO:0000269|PubMed:19306925, ECO:0000269|PubMed:20005108}.;
Recessive Scores
- pRec
- 0.315
Intolerance Scores
- RVIS EVS
- 0.32
- RVIS percentile EVS
- 72.94
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.958
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Medium |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |