RALA

Summary

RALA (RAS like proto-oncogene A, HGNC:9839) is a protein-coding gene on chromosome 7p14.1, encoding Ras-related protein Ral-A (P11233). Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking.

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.

Source: NCBI Gene 5898 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 129 total — 5 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• MANE Select transcript: NM_005402

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9839
Approved symbol	RALA
Name	RAS like proto-oncogene A
Location	7p14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000006451
Ensembl biotype	protein_coding
OMIM	179550
Entrez	5898

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000005257, ENST00000434466, ENST00000436179, ENST00000466491, ENST00000468201, ENST00000860175, ENST00000860176, ENST00000860177, ENST00000860178, ENST00000860179, ENST00000860180, ENST00000919558, ENST00000919559, ENST00000957819, ENST00000957820, ENST00000957821, ENST00000957822, ENST00000957823

RefSeq mRNA: 1 — MANE Select: NM_005402 NM_005402

CCDS: CCDS5460

Canonical transcript exons

ENST00000005257 — 5 exons

Exon	Start	End
ENSE00000679279	39690382	39690590
ENSE00000832451	39686631	39686781
ENSE00001270055	39706123	39708120
ENSE00001829077	39623572	39623825
ENSE00003620166	39696685	39696859

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 70.6372 / max 1160.9296, expressed in 1822 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78255	40.1905	1817
78258	22.2700	1766
78257	5.3110	1590
78261	0.9350	466
78259	0.6877	326
78256	0.4191	222
78260	0.3975	243
78254	0.3304	119
78262	0.0961	46

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	98.59	gold quality
secondary oocyte	CL:0000655	98.53	gold quality
buccal mucosa cell	CL:0002336	98.33	gold quality
amniotic fluid	UBERON:0000173	98.20	gold quality
oral cavity	UBERON:0000167	98.13	gold quality
gingival epithelium	UBERON:0001949	97.93	gold quality
gingiva	UBERON:0001828	97.91	gold quality
pharyngeal mucosa	UBERON:0000355	97.79	gold quality
squamous epithelium	UBERON:0006914	97.71	gold quality
epithelium of esophagus	UBERON:0001976	97.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.21	gold quality
skin of hip	UBERON:0001554	96.96	gold quality
visceral pleura	UBERON:0002401	96.85	gold quality
middle temporal gyrus	UBERON:0002771	96.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.80	gold quality
colonic mucosa	UBERON:0000317	96.74	gold quality
cortical plate	UBERON:0005343	96.35	gold quality
parotid gland	UBERON:0001831	96.27	gold quality
lower esophagus mucosa	UBERON:0035834	96.18	gold quality
endothelial cell	CL:0000115	96.14	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.10	gold quality
substantia nigra pars compacta	UBERON:0001965	96.06	gold quality
jejunal mucosa	UBERON:0000399	95.86	gold quality
tongue squamous epithelium	UBERON:0006919	95.76	gold quality
mammalian vulva	UBERON:0000997	95.75	gold quality
medial globus pallidus	UBERON:0002477	95.74	gold quality
mammary duct	UBERON:0001765	95.70	gold quality
ganglionic eminence	UBERON:0004023	95.67	gold quality
globus pallidus	UBERON:0001875	95.66	gold quality
entorhinal cortex	UBERON:0002728	95.61	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	833.22
E-MTAB-8142	yes	73.84
E-CURD-114	yes	10.60
E-MTAB-7381	no	362.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

214 targeting RALA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-3910	99.95	71.13	2227

Literature-anchored findings (GeneRIF, showing 40)

• differential binding of calmodulin by RalA and RalB (PMID:12034722)
• RALA and RALB collaborate to maintain tumorigenicity through regulation of both proliferation and survival; RALA is dispensable for survival, but is required for anchorage-independent proliferation (PMID:12856001)
• Protein kinase A-dependent activation of Ral regulates cAMP-mediated exocytosis of Weibel-Palade bodies in endothelial cells. (PMID:15130921)
• crystal structure of Clostridium botulinum C3bot1 in complex with RalA (a GTPase of the Ras subfamily) and GDP at a resolution of 2.66 A (PMID:15809419)
• the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-delta1 activation (PMID:15817490)
• Activation of RalA signaling appears to be a critical step in Ras-induced transformation and tumorigenesis of human cells. (PMID:15950903)
• androgen deprivation of human prostate carcinoma cells activates the small GTPase, RalA, a molecule important for human oncogenesis (PMID:16964283)
• study concludes RalA function is critical to tumor initiation, while RalB is more important for tumor metastasis in the tested pancreatic carcinoma cell lines & argues for critical roles of Ral proteins during progression of Ras-driven pancreatic cancers (PMID:17174914)
• Ral is activated upon BCR stimulation and mediates BCR-controlled activation of AP-1 and NFAT transcription factors. (PMID:17237388)
• Results suggest that Rab5 and RalA regulate P-gp trafficking between the plasma membrane and an intracellular compartment. (PMID:17524504)
• These observations identify PP2A Abeta as a tumor suppressor gene that transforms immortalized human cells by regulating the function of RalA. (PMID:17540176)
• analysis of activation and differential expression of RalA and RalB in human bladder cancer (PMID:17606711)
• These data extend understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis. (PMID:17709381)
• Data suggest that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition. (PMID:17875936)
• RalA and RalB support mitotic progression through mobilization of the exocyst for two spatially and kinetically distinct steps of cytokinesis (PMID:18756269)
• RalGDS and RalA act downstream of Rheb and RalA activation is a crucial step in nutrient-induced mTORC1 activation (PMID:18948269)
• These results establish RalA and GRK2 as key regulators of LPA receptor signalling and demonstrate for the first time that LPA(1) activity facilitates the formation of a novel protein complex between these two proteins. (PMID:19306925)
• RalA was overactivated in all malignant peripheral nerve sheath tumor cells and tumor samples compared to nontransformed Schwann cells. (PMID:19414599)
• Data show that conversion of Ras-expressing keratinocytes from a premalignant to malignant state induced by decreasing E-cadherin function was associated with and required an approximately two to threefold decrease in RalA expression. (PMID:19802010)
• Data suggest that RalA might contribute to liver malignant transformation, and could be used as a potential tumor marker in hepatocellular carcinoma detection. (PMID:19822090)
• Aurora-A may converge upon oncogenic Ras signaling through RalA. (PMID:19901077)
• Expression of the small GTPase RalA is required for angiotensin II type I receptor-stimulated inositol phosphate formation. (PMID:20018811)
• RalA is activated by Salmonella infection in a SopE-dependent manner, and is required for exocyst assembly. (PMID:20579884)
• studies suggest that the expression of RalBP1 is necessary for human cancer cell metastasis; show that the requirement for RalA expression for manifestation of this phenotype is not entirely dependent on a RalA-RalBP1 interaction (PMID:21170262)
• RalA interaction with the Exo84 but not Sec5 exocyst component was necessary for supporting anchorage-independent growth, whereas RalB interaction with Sec5 but not Exo84 was necessary for inhibition of anchorage-independent growth (PMID:21199803)
• Ral is a critical regulator in PMN that specifically controls secondary granule release during PMN response to chemoattractant stimulation. (PMID:21282111)
• RalA, the binding partner of PKC eta, is involved in not only the keratinocyte differentiation induced by PKCeta overexpression but also in normal keratinocyte differentiation induced by calcium and cholesterol sulfate. (PMID:21346190)
• conclude that the ability of hRgr to activate both Ral and Ras is responsible for its transformation-inducing phenotype and it could be an important contributor in the development of some T-cell malignancies (PMID:21441953)
• Correlation between RalA protein expression decrease and absence of regional metastases was revealed for squamous cell lung cancer. (PMID:21634118)
• The RalA was not only cytoprotective against multiple chemotherapeutic drugs, but also promigratory inducing stress fiber formation, which was accompanied by the activation of Akt and Erk pathways. (PMID:21645515)
• Our results identify a role for RalA and RalB in cell-mediated cytotoxicity (PMID:21810610)
• Data show that disrupting either RALA or RALBP1 leads to a loss of mitochondrial fission at mitosis, improper segregation of mitochondria during cytokinesis and a decrease in ATP levels and cell number. (PMID:21822277)
• RalA and RalB differentially regulate development of epithelial tight junctions. (PMID:22013078)
• This study detected RALA level in Chronic myelogenous leukemia cells, which is highly expressed and distributed mainly in the cytoplasm and/or partially in endomembrane. (PMID:22330069)
• RalA is directly regulated by miR-181a and plays an important role in CML. (PMID:22442671)
• Targeted interference of EP2/EP4 signal to RalA.GTP may provide benefit to patients diagnosed with advanced kidney cancer. (PMID:22580611)
• the existence of an ubiquitination/de-ubiquitination cycle superimposed on the GDP/GTP cycle of RalA, involved in the regulation of RalA activity as well as in membrane raft trafficking. (PMID:22700969)
• We identified interactions between RalA and its effectors sec5 and exo84 in the Exocyst complex as directly necessary for migration and invasion of prostate cancer tumor cells. (PMID:22761837)
• The study found upregulated RalA and RalB activation in colorectal cancer tumor cell lines and tumors. (PMID:22790202)
• Data show that small GTPase RALA regulates formation of a JIP1 (C-Jun-amino-terminal-interacting protein 1) scaffold complex to propagate JNK signaling toward FOXO4 (forkhead box O transcription factor) in response to reactive oxygen species (ROS). (PMID:23770673)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ralab	ENSDARG00000016253
danio_rerio	ralaa	ENSDARG00000045463
mus_musculus	Rala	ENSMUSG00000008859
rattus_norvegicus	Rala	ENSRNOG00000013454

Paralogs (35): REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), RASL11B (ENSG00000128045), KRAS (ENSG00000133703), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

Ras-related protein Ral-A — P11233 (reviewed: P11233)

All UniProt accessions (3): P11233, C9JPE8, H7C3P7

UniProt curated annotations — full annotation on UniProt →

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. 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. 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. During mitosis, also controls mitochondrial fission by recruiting to the mitochondrion RALBP1, which mediates the phosphorylation and activation of DNM1L by the mitotic kinase cyclin B-CDK1.

Subunit / interactions. Interacts (via effector domain) with RALBP1; during mitosis, recruits RALBP1 to the mitochondrion where it promotes DNM1L phosphorylation and mitochondrial fission. Interacts with EXOC2/Sec5 and EXOC8/Exo84; binding to EXOC2 and EXOC8 is mutually exclusive. Interacts with Clostridium exoenzyme C3. Interacts with RALGPS1. Interacts with LPAR1 and LPAR2. Interacts with GRK2 in response to LPAR1 activation. RALA and GRK2 binding to LPAR1 is mutually exclusive. Interacts with CDC42.

Subcellular location. Cell membrane. Cleavage furrow. Midbody. Midbody ring. Mitochondrion.

Post-translational modifications. Phosphorylated. Phosphorylation at Ser-194 by AURKA/Aurora kinase A, during mitosis, induces RALA localization to the mitochondrion where it regulates mitochondrial fission. Prenylation is essential for membrane localization. The geranylgeranylated form and the farnesylated mutant do not undergo alternative prenylation in response to geranylgeranyltransferase I inhibitors (GGTIs) and farnesyltransferase I inhibitors (FTIs). (Microbial infection) Glucosylated at Thr-46 by P.sordellii toxin TcsL from strain 6018. Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form. Not glucosylated by TcsL from strain VPI 9048.

Disease relevance. Hiatt-Neu-Cooper neurodevelopmental syndrome (HINCONS) [MIM:619311] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, delayed walking or inability to walk, impaired intellectual development, poor or absent speech, axial hypotonia, and facial dysmorphism. Additional variable features may include seizures, autistic or behavioral abnormalities, and brain abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).

Induction. Activated in an LPA-dependent manner by LPAR1 and in an LPA-independent manner by LPAR2.

Similarity. Belongs to the small GTPase superfamily. Ras family.

RefSeq proteins (1): NP_005393* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (53 total): mutagenesis site 20, sequence variant 7, strand 7, helix 6, binding site 3, turn 2, modified residue 2, chain 1, propeptide 1, short sequence motif 1, sequence conflict 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
6P0I	X-RAY DIFFRACTION	1.18
6P0L	X-RAY DIFFRACTION	1.3
6P0J	X-RAY DIFFRACTION	1.31
8FJI	X-RAY DIFFRACTION	1.48
6P0K	X-RAY DIFFRACTION	1.49
6P0M	X-RAY DIFFRACTION	1.5
6P0O	X-RAY DIFFRACTION	1.54
8FJH	X-RAY DIFFRACTION	1.54
6P0N	X-RAY DIFFRACTION	1.63
2A9K	X-RAY DIFFRACTION	1.73
2A78	X-RAY DIFFRACTION	1.81
1ZC3	X-RAY DIFFRACTION	2
1UAD	X-RAY DIFFRACTION	2.1
1ZC4	X-RAY DIFFRACTION	2.5
2BOV	X-RAY DIFFRACTION	2.66
7NQC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11233-F1	89.54	0.73

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 24–29; 40–46; 127–130

Post-translational modifications (3): 194, 203, 203

Glycosylation sites (1): 46

Mutagenesis-validated functional residues (20):

Position	Phenotype
1–11	impaired cytokinesis, as shown by increased number of binucleate cells. impaired cytokinesis; when associated with l-72.
23	impaired cytokinesis, as shown by increased number of binucleate cells. no effect on interaction with exoc2 and exoc8. n
38	impaired cytokinesis, as shown by increased number of binucleate cells. no effect on cytokinesis; when associated with v
46	abolished monoglucosylation by p.sordellii toxin tcsl.
47	strongly reduces interaction with exoc8.
47	no effect on interaction with exoc8.
48	impaired cytokinesis, as shown by increased number of binucleate cells. no effect on cytokinesis; when associated with v
48	strongly reduces interaction with exoc8.
49	no effect on cytokinesis; when associated with l-72.
49	no effect on cytokinesis. impaired cytokinesis, as shown by increased number of binucleate cells; when associated with l
50	strongly reduces interaction with exoc8.
52	strongly reduces interaction with exoc8.
52	no effect on interaction with exoc8.
72	impaired cytokinesis, as shown by increased number of binucleate cells. impaired cytokinesis; when associated with n-49
81	no effect on interaction with exoc8.
81	strongly reduces interaction with exoc8.
194	decreased localization to mitochondrion. loss of function in mitochondrial fission.
194	increased localization to mitochondrion.
203	loss of geranylgeranylation and membrane localization.
206	converts geranyl-geranylation to farnesylation. no effect on membrane localization. fails to deflect ggti-induced apopto

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-171007	p38MAPK events
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation

MSigDB gene sets: 464 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GGTGTGT_MIR329, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_REGULATION_OF_EXOCYTOSIS, GOCC_CELL_SURFACE, TATTATA_MIR374

GO Biological Process (15): neural tube closure (GO:0001843), exocytosis (GO:0006887), chemotaxis (GO:0006935), signal transduction (GO:0007165), Ras protein signal transduction (GO:0007265), regulation of exocytosis (GO:0017157), receptor internalization (GO:0031623), regulation of actin cytoskeleton organization (GO:0032956), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), cell division (GO:0051301), positive regulation of filopodium assembly (GO:0051491), membrane raft localization (GO:0051665), obsolete establishment of protein localization to mitochondrion (GO:0072655), positive regulation of mitochondrial fission (GO:0090141), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149)

GO Molecular Function (11): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), myosin binding (GO:0017022), GDP binding (GO:0019003), ubiquitin protein ligase binding (GO:0031625), Edg-2 lysophosphatidic acid receptor binding (GO:0031755), ATPase binding (GO:0051117), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (14): mitochondrion (GO:0005739), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell surface (GO:0009986), cytoplasmic vesicle membrane (GO:0030659), cleavage furrow (GO:0032154), extracellular exosome (GO:0070062), Flemming body (GO:0090543), synaptic membrane (GO:0097060), Schaffer collateral - CA1 synapse (GO:0098685), endomembrane system (GO:0012505), membrane (GO:0016020), endocytic vesicle (GO:0030139), midbody (GO:0030496)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Membrane Trafficking	1
Signalling to RAS	1
Interleukin-12 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cellular process	2
guanyl ribonucleotide binding	2
cytoplasmic vesicle	2
plasma membrane region	2
synapse	2
primary neural tube formation	1
tube closure	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
response to chemical	1
taxis	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
receptor-mediated endocytosis	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
positive regulation of ERBB signaling pathway	1
filopodium assembly	1
regulation of filopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
localization within membrane	1
mitochondrial fission	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
ribonucleoside triphosphate phosphatase activity	1

Protein interactions and networks

STRING

3108 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RALA	RALBP1	Q15311	998
RALA	EXOC8	Q8IYI6	995
RALA	EXOC2	Q96KP1	993
RALA	RALGDS	Q12967	988
RALA	RASA1	P20936	987
RALA	FLNA	P21333	906
RALA	LRPAP1	P30533	881
RALA	EXOC4	Q96A65	874
RALA	RGL1	Q9NZL6	853
RALA	EXOC1	Q9NV70	847
RALA	RGL4	Q8IZJ4	844
RALA	PPP2R1B	P30154	832
RALA	EXOC6B	Q9Y2D4	804
RALA	FLNC	Q14315	787
RALA	FLNB	O75369	785

IntAct

92 interactions, top by confidence:

A	B	Type	Score
PPP2R1B	STRN	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RALBP1	RALA	psi-mi:“MI:0914”(association)	0.690
RALBP1	RALA	psi-mi:“MI:0915”(physical association)	0.690
RALA	RALBP1	psi-mi:“MI:2364”(proximity)	0.690
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
Exoc2	RALA	psi-mi:“MI:0407”(direct interaction)	0.590
Exoc2	RALA	psi-mi:“MI:0914”(association)	0.590
RALA	CALM1	psi-mi:“MI:0407”(direct interaction)	0.590
CALM1	RALA	psi-mi:“MI:0915”(physical association)	0.590
RALA	CALM1	psi-mi:“MI:0915”(physical association)	0.590
RALA	HRAS	psi-mi:“MI:0407”(direct interaction)	0.570
rep	AGPS	psi-mi:“MI:0914”(association)	0.530
RALA	PPP2R1B	psi-mi:“MI:0915”(physical association)	0.500
PPP2R1B	RALA	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
RALA	C3	psi-mi:“MI:0407”(direct interaction)	0.440
RBMXL2	RALA	psi-mi:“MI:0915”(physical association)	0.400
DDN	RALA	psi-mi:“MI:0915”(physical association)	0.400
RALA	DNAJB11	psi-mi:“MI:0915”(physical association)	0.400
RALA	ZBTB10	psi-mi:“MI:0915”(physical association)	0.400
RALA	SMC3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (203): RALA (Affinity Capture-MS), RALA (Affinity Capture-MS), RALA (Affinity Capture-MS), RALA (Affinity Capture-MS), RALA (Two-hybrid), RALA (Affinity Capture-MS), RALA (Two-hybrid), GLS2 (Reconstituted Complex), ATP5J (Affinity Capture-MS), FLNB (Affinity Capture-MS), GPT (Affinity Capture-MS), MCM5 (Affinity Capture-MS), RALA (Affinity Capture-MS), RALA (Affinity Capture-MS), RALA (Affinity Capture-MS)

ESM2 similar proteins: C9WPN6, F1QGW6, O14787, O77676, P00514, P00516, P07802, P09456, P0C605, P10644, P11233, P12849, P20461, P31321, P35250, P41091, P49136, P53033, P61964, P62482, P62483, P63320, P63321, P63322, P81377, P81795, Q05B83, Q13303, Q13976, Q27955, Q2KHU8, Q2KIG2, Q2VIR3, Q3SYU7, Q498M4, Q5I0F6, Q5M786, Q5R797, Q5REL1, Q5ZM91

Diamond homologs: A1DZY4, A6QP66, A8NU18, C4YKT4, O08989, O14807, O35929, O88667, O93856, O94363, P01119, P03967, P08645, P08647, P0CY32, P10114, P10536, P11233, P11234, P15064, P17609, P22124, P22126, P22278, P22279, P22280, P28775, P32254, P36860, P36863, P48555, P59279, P61105, P61225, P61226, P61227, P62070, P62071, P63320, P63321

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PPP2CB	down-regulates	RALA	dephosphorylation
AURKA	“up-regulates activity”	RALA	phosphorylation
RALA	“up-regulates activity”	FOXO4	phosphorylation
RALA	“up-regulates activity”	FOXO	phosphorylation
RalGAP1	“down-regulates activity”	RALA	“guanine nucleotide exchange factor”
RalGAP2	“down-regulates activity”	RALA	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF activation	5	26.7×	2e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	12.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	5	46.2×	5e-05
response to calcium ion	5	21.8×	5e-04
Ras protein signal transduction	5	14.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

129 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	8
Uncertain significance	46
Likely benign	51
Benign	12

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1068752	NM_005402.4(RALA):c.73G>T (p.Val25Leu)	Pathogenic
1068753	NM_005402.4(RALA):c.389A>G (p.Asp130Gly)	Pathogenic
1068754	NM_005402.4(RALA):c.469T>G (p.Ser157Ala)	Pathogenic
1700118	NM_005402.4(RALA):c.470C>T (p.Ser157Phe)	Pathogenic
3062975	GRCh37/hg19 7p14.1(chr7:38484106-42786613)x1	Pathogenic
1320180	NM_005402.4(RALA):c.404_429dup (p.Asn144delinsAspArgPheLeuTer)	Likely pathogenic
1335663	NM_005402.4(RALA):c.383A>G (p.Lys128Arg)	Likely pathogenic
1804032	NM_005402.4(RALA):c.472G>A (p.Ala158Thr)	Likely pathogenic
2574156	NM_005402.4(RALA):c.467C>T (p.Thr156Ile)	Likely pathogenic
2582518	NM_005402.4(RALA):c.46A>G (p.Lys16Glu)	Likely pathogenic
2626855	NM_005402.4(RALA):c.68G>C (p.Gly23Ala)	Likely pathogenic
3893366	NM_005402.4(RALA):c.128A>G (p.Tyr43Cys)	Likely pathogenic
872219	NM_005402.4(RALA):c.390T>A (p.Asp130Glu)	Likely pathogenic

SpliceAI

1325 predictions. Top by Δscore:

Variant	Effect	Δscore
7:39645154:C:CG	donor_gain	1.0000
7:39645154:C:G	donor_gain	1.0000
7:39686778:TGAGG:T	donor_loss	1.0000
7:39686779:GAGGT:G	donor_loss	1.0000
7:39686781:GGT:G	donor_loss	1.0000
7:39686783:T:G	donor_loss	1.0000
7:39690378:CTAGT:C	acceptor_loss	1.0000
7:39690380:A:AG	acceptor_gain	1.0000
7:39690380:AGTTT:A	acceptor_gain	1.0000
7:39690381:G:GA	acceptor_gain	1.0000
7:39690381:GT:G	acceptor_gain	1.0000
7:39690381:GTT:G	acceptor_gain	1.0000
7:39690381:GTTT:G	acceptor_gain	1.0000
7:39690381:GTTTG:G	acceptor_gain	1.0000
7:39690586:TTCAG:T	donor_loss	1.0000
7:39690587:TCAGG:T	donor_loss	1.0000
7:39690588:CAG:C	donor_loss	1.0000
7:39690589:AGGTA:A	donor_loss	1.0000
7:39690590:GGTA:G	donor_loss	1.0000
7:39690591:G:T	donor_loss	1.0000
7:39690592:T:A	donor_loss	1.0000
7:39696670:T:G	acceptor_gain	1.0000
7:39696679:A:AG	acceptor_gain	1.0000
7:39696683:A:AG	acceptor_gain	1.0000
7:39696683:AG:A	acceptor_gain	1.0000
7:39696683:AGG:A	acceptor_gain	1.0000
7:39696684:G:A	acceptor_gain	1.0000
7:39696684:G:GC	acceptor_gain	1.0000
7:39696684:GGG:G	acceptor_gain	1.0000
7:39696684:GGGA:G	acceptor_gain	1.0000

AlphaMissense

1367 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:39686728:G:C	G21R	1.000
7:39686729:G:A	G21D	1.000
7:39686729:G:T	G21V	1.000
7:39686743:G:C	G26R	1.000
7:39686743:G:T	G26C	1.000
7:39686744:G:A	G26D	1.000
7:39686744:G:T	G26V	1.000
7:39686746:A:C	K27Q	1.000
7:39686748:G:C	K27N	1.000
7:39686748:G:T	K27N	1.000
7:39686750:C:T	S28L	1.000
7:39686756:T:C	L30P	1.000
7:39686762:T:C	L32P	1.000
7:39690382:T:C	F39L	1.000
7:39690383:T:C	F39S	1.000
7:39690383:T:G	F39C	1.000
7:39690384:T:A	F39L	1.000
7:39690384:T:G	F39L	1.000
7:39690464:T:A	I66N	1.000
7:39690469:G:A	D68N	1.000
7:39690469:G:C	D68H	1.000
7:39690470:A:C	D68A	1.000
7:39690470:A:G	D68G	1.000
7:39690470:A:T	D68V	1.000
7:39690471:T:A	D68E	1.000
7:39690471:T:G	D68E	1.000
7:39690476:C:A	A70D	1.000
7:39690478:G:A	G71R	1.000
7:39690478:G:C	G71R	1.000
7:39690478:G:T	G71W	1.000

dbSNP variants (sampled 300 via entrez): RS1000004013 (7:39708231 C>G,T), RS1000061975 (7:39660407 T>C), RS1000139999 (7:39639501 A>C,G), RS1000177514 (7:39699382 C>G), RS1000196028 (7:39623913 G>T), RS1000238179 (7:39702553 A>G), RS1000274046 (7:39664708 T>C), RS1000277671 (7:39678466 A>G), RS1000305589 (7:39624469 A>G), RS1000432371 (7:39692923 A>G), RS1000444355 (7:39626800 G>A), RS1000444417 (7:39648930 G>A), RS1000448796 (7:39671339 G>A), RS1000479841 (7:39670993 G>A), RS1000524118 (7:39645544 T>C)

Disease associations

OMIM: gene MIM:179550 | disease phenotypes: MIM:619311, MIM:163950

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
Hiatt-Neu-Cooper neurodevelopmental syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (4): Hiatt-Neu-Cooper neurodevelopmental syndrome (MONDO:0859142), Noonan syndrome 1 (MONDO:0008104), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Noonan syndrome (Orphanet:648), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000219	Thin upper lip vermilion
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000322	Short philtrum
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000508	Ptosis
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0002263	Exaggerated cupid’s bow
HP:0003577	Congenital onset
HP:0004691	2-3 toe syndactyly
HP:0011220	Prominent forehead
HP:0011228	Horizontal eyebrow
HP:0030084	Clinodactyly
HP:0031936	Delayed ability to walk

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3879855 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

75 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, affects expression, decreases expression	5
Cadmium Chloride	decreases expression, increases abundance, increases expression	4
bisphenol S	increases expression, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases expression	3
sodium arsenite	affects expression, increases expression	2
Arsenic Trioxide	increases expression, decreases response to substance	2
Cadmium	increases abundance, increases expression	2
Estradiol	decreases expression, increases expression, decreases reaction	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	affects cotreatment, increases expression	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	decreases reaction, increases expression, decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression	1
ochratoxin A	affects binding	1
beta-methylcholine	affects expression	1
nefazodone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
10-decarbamoylmitomycin C	decreases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
CGP 52608	increases reaction, affects binding	1
chloropicrin	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3870848	Binding	Inhibition of RalA activity in human H2122 spheroids after 4 hrs by RalBP1 pull down assay	Synthesis of novel Ral inhibitors: An in vitro and in vivo study. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2DA	Abcam HeLa RALA KO	Cancer cell line	Female

Clinical trials (associated diseases)

199 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1