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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
RALGAPA1
Ral GTPase activating protein catalytic subunit alpha 1
Chromosome 14 Β· 14q13.2
NCBI Gene: 253959Ensembl: ENSG00000174373.17HGNC: HGNC:17770UniProt: A0A1B0GUI1
57PubMed Papers
21Diseases
0Drugs
12Pathogenic Variants
FUNCTIONAL ROLE
Highly Constrained
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein heterodimerization activitysmall GTPase-mediated signal transductionGTPase activator activitynucleusneurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationneurodegenerative diseasegenetic disorderNeurodevelopmental disorder
✦AI Summary

RALGAPA1 encodes the catalytic subunit of the RalGAP1 complex, which functions as a GTPase-activating protein for the small GTPases RALA and RALB, negatively regulating their signaling activity 1. Loss-of-function variants in RALGAPA1 result in constitutive RALA activation and dysfunctional RalGAP complex assembly, with dramatic reduction of the scaffolding subunit RalGAPB 1. This dysregulation disrupts cell-surface lipid raft organization and anchorage-dependent signaling 1. RalGAPA1 deficiency causes profound neurodevelopmental disability characterized by intellectual disability, infantile spasms, muscular hypotonia, corpus callosum dysplasia, and feeding abnormalities, representing a distinct group of genetic syndromes termed "RALopathies" 1. The gene is highly expressed in brain tissue and critical for normal neuronal development 2. Animal models confirm that RALGAPA1 knockdown causes developmental delay 2. Additionally, RALGAPA1 regulates GLUT4 glucose transporter expression in muscle fibers, with loss-of-function variants causing glycogen storage myopathy 3. Beyond neurological disease, RALGAPA1 appears to function as a tumor suppressor gene in glioblastoma and pan-cancer contexts 4, with mutations associated with increased malignancy in lung adenocarcinoma 5. Population genetics studies identify RALGAPA1 as a specific genetic predisposing factor to elevated body mass index in East Asian populations 6.

Sources cited
1
RALGAPA1 bi-allelic variants cause neurodevelopmental disability, hypotonia, infantile spasms; RalGAPA1 deficiency increases RalA activity and reduces RalGAPB levels; disrupts lipid raft organization
PMID: 32004447
2
RALGAPA1 haploinsufficiency associated with developmental delay and epilepsy; highly expressed in brain; knockdown in zebrafish causes brain developmental delay
PMID: 19733229
3
RALGAPA1 deletion causes neonatal hypotonia and glycogen storage myopathy through effects on GLUT4 expression in muscle fibers
PMID: 37743183
4
RALGAPA1 identified as tumor suppressor gene in glioblastoma and pan-cancer through multi-omics analysis
PMID: 40249536
5
RALGAPA1 gene expression differences detected in lung adenocarcinoma co-existing with tuberculosis; mutations correlate with higher malignancy
PMID: 40061944
6
RALGAPA1 identified as specific genetic predisposing factor to high BMI in Taiwanese population through GWAS
PMID: 35051171
7
RALGAPA1 deletion in Belgian shepherd dogs causes cerebellar ataxia with Purkinje cell pathology; demonstrates conserved function across species
PMID: 37628572
Disease Associationsβ“˜21
neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationOpen Targets
0.73Strong
neurodegenerative diseaseOpen Targets
0.50Moderate
genetic disorderOpen Targets
0.42Moderate
Neurodevelopmental disorderOpen Targets
0.37Weak
sleep apneaOpen Targets
0.37Weak
ovarian neoplasmOpen Targets
0.31Weak
ovarian dysfunctionOpen Targets
0.30Weak
ArthropathyOpen Targets
0.30Weak
obstructive sleep apneaOpen Targets
0.26Weak
placental retentionOpen Targets
0.25Weak
hypothyroidismOpen Targets
0.14Weak
nontoxic goiterOpen Targets
0.12Weak
multinodular goiterOpen Targets
0.09Suggestive
thyroid cancerOpen Targets
0.08Suggestive
papillary thyroid carcinomaOpen Targets
0.07Suggestive
diaphragm diseaseOpen Targets
0.07Suggestive
migraine disorderOpen Targets
0.07Suggestive
obesity due to melanocortin 4 receptor deficiencyOpen Targets
0.06Suggestive
attention deficit hyperactivity disorderOpen Targets
0.06Suggestive
thyroid neoplasmOpen Targets
0.06Suggestive
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulationUniProt
Pathogenic Variants12
NM_001346249.2(RALGAPA1):c.1952C>A (p.Ser651Ter)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 651
NM_001346249.2(RALGAPA1):c.1126C>T (p.Arg376Ter)Pathogenic
Feeding difficulties|Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation|not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 376
NM_001346249.2(RALGAPA1):c.3152T>G (p.Leu1051Ter)Likely pathogenic
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜…β˜†β˜†β˜†2023β†’ Residue 1051
NM_001346249.2(RALGAPA1):c.5042_5043dup (p.Met1682Ter)Likely pathogenic
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜…β˜†β˜†β˜†2023β†’ Residue 1682
NM_001346249.2(RALGAPA1):c.1409_1410del (p.Asp470fs)Pathogenic
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜…β˜†β˜†β˜†2022β†’ Residue 470
NM_001346249.2(RALGAPA1):c.5455C>T (p.Gln1819Ter)Pathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2021β†’ Residue 1819
NM_001346249.2(RALGAPA1):c.7152_7155dup (p.Phe2386fs)Likely pathogenic
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜…β˜†β˜†β˜†β†’ Residue 2386
NM_001346249.2(RALGAPA1):c.1449+1G>TLikely pathogenic
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜…β˜†β˜†β˜†
NM_001346249.2(RALGAPA1):c.6510del (p.Phe2170fs)Pathogenic
Feeding difficulties|Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜†β˜†β˜†β˜†2020β†’ Residue 2170
NM_001346249.2(RALGAPA1):c.610G>T (p.Glu204Ter)Pathogenic
Feeding difficulties|Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜†β˜†β˜†β˜†2020β†’ Residue 204
NM_001346249.2(RALGAPA1):c.7250C>G (p.Ser2417Ter)Pathogenic
Feeding difficulties|Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜†β˜†β˜†β˜†2020β†’ Residue 2417
NM_001346249.2(RALGAPA1):c.4745A>G (p.Asn1582Ser)Pathogenic
Feeding difficulties|Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
β˜†β˜†β˜†β˜†2020β†’ Residue 1582
View on ClinVar β†—
Related Genes
NKIRAS2Protein interaction83%LRPAP1Protein interaction81%RALGAPBProtein interaction77%ARHGAP31Shared pathway67%ARHGAP9Shared pathway67%RALGAPA2Shared pathway67%
Tissue Expression6 tissues
Brain
100%
Ovary
71%
Bone Marrow
38%
Lung
38%
Heart
33%
Liver
32%
Gene Interaction Network
Click a node to explore
RALGAPA1NKIRAS2LRPAP1RALGAPBARHGAP31ARHGAP9RALGAPA2
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q6GYQ0
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.29Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.22 [0.16–0.29]
RankingsWhere RALGAPA1 stands among ~20K protein-coding genes
  • #8,002of 20,598
    Most Researched57
  • #2,687of 5,498
    Most Pathogenic Variants12
  • #1,079of 17,882
    Most Constrained (LOEUF)0.29 Β· top 10%
Genes detectedRALGAPA1
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Identification of SURF4 and RALGAPA1 as promising therapeutic targets in glioblastoma and pan-cancer through integrative multi-omics, CRISPR-Cas9 screening and prognostic meta-analysis.
PMID: 40249536
Cancer Immunol Immunother Β· 2025
1.00
2
PMID: 40061944
Front Immunol Β· 2025
0.90
3
Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.
PMID: 32004447
Am J Hum Genet Β· 2020
0.80
4
Whole‑exome sequencing insights into synchronous bilateral breast cancer with discordant molecular subtypes.
PMID: 39430730
Oncol Lett Β· 2024
0.70
5
PMID: 37628572
Genes (Basel) Β· 2023
0.60