SLC38A9
protein-codingsolute carrier family 38 member 9, the group of Solute carrier family 38
Gene summary
Enables several functions, including L-amino acid transmembrane transporter activity; cholesterol binding activity; and guanyl-nucleotide exchange factor activity. Involved in carboxylic acid transport; cellular response to amino acid stimulus; and positive regulation of TORC1 signaling. Located in Ragulator complex; late endosome; and lysosomal membrane. Part of FNIP-folliculin RagC/D GAP. [provided by Alliance of Genome Resources, Jul 2025]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~147.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0002561
Submitter: ClinGen
The relationship between the SLC38A9 gene and lysosomal storage disorders was evaluated using the ClinGen Clinical Validity Framework as of July 21, 2022. SLC38A9 encodes solute carrier family 38, member 9, a lysosomal amino acid transporter protein involved in regulating the mechanistic target of rapamycin complex 1 (mTORC1), via modulating transport of amino acids that stimulate mTORC1 activation (PMID: 25561175, PMID: 25567906) and mediating cholesterol-driven mTORC1 activation (PMID: 28336668). To our knowledge, SLC38A9 has not been reported in association with human disease to date. Based on published experimental data, there is minimal evidence suggesting a role for SLC38A9 in lysosomal storage disorders. This experimental evidence (4.50 points total) includes: the biochemical function of the gene product (solute carrier family 38, member 9) being consistent with altered amino acid-mediated signaling of mTORC1 (PMID: 25561175); the physical interaction between SLC38A9 and NPC intracellular cholesterol transporter 1 (PMID: 28336668), a protein encoded by the NPC1 gene, which has been curated as Definitively associated with the lysosomal storage disease Niemann-Pick disease type C1 by the ClinGen Lysosomal Diseases GCEP; functional alteration (impaired amino acid-mediated signaling of mTORC1 in HEK293T cells harboring SLC38A9 variants lacking key amino acid residues involved in interacting with the Ragulator complex (PMID: 25567906); rescue of HEK293T cells harboring SLC38A9 variants lacking key amino acid residues involved in interacting with the Ragulator complex by reexpression of the segment containing these residues (PMID: 25567906); and the abnormal amino acid metabolism seen in a SLC38A9 knockout zebrafish model (PMID: 35457018). In summary, there is currently no direct evidence supporting the association between the SLC38A9 gene and lysosomal storage disorders. There is minimal experimental evidence suggesting that the SLC38A9 gene may play a role in lysosomal storage disorders via its role in regulating mTORC1, but additional publications, including those involving human cases, are needed to define the role of the SLC38A9 gene in lysosomal storage disorders. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on August 2, 2022 (SOP v9).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC38A9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_173514.4. 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 | 1 | ||||
| missense | 59 | 2 | 1 | 62 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 66 | 2 | 1 | 69 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_775785.2 | 14 | MANE Select | |
| Ensembl | ENSP00000380074.2 | 14 | MANE Select | |
| RefSeq | NP_001245215.1 | 13 | Standard | |
| RefSeq | NP_001245216.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- mTOR signaling pathway - Homo sapiens (human)
- Signal Transduction
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
Biological Process
- amino acid transmembrane transport
- cell cycle arrest
- regulation of macroautophagy
- positive regulation of TOR signaling
- cellular response to amino acid stimulus
Molecular Function
- protein binding
- amino acid transmembrane transporter activity
Cellular Component
- nucleoplasm
- lysosome
- lysosomal membrane
- late endosome
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396865
- Coding exons
- 14
- Length
- 147350
- Individuals with no LoFs
- 125709
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 39
- Defined
- 125748
- p
- 0.000155
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.48 | 222 | 293 | 0.757 | 0.0000141 | 3712 |
| Missense (PolyPhen) | 68 | 86.837 | 0.78307 | 1136 | ||
| Synonymous | 1.26 | 85 | 101 | 0.841 | 0.00000505 | 1042 |
| Loss of Function | 3.59 | 6 | 25.6 | 0.235 | 0.00000108 | 343 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00022 | 0.00020 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00098 | 0.00098 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000073 | 0.000070 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0.00019 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Lysosomal amino acid transporter involved in the activation of mTORC1 in response to amino acids. Probably acts as an amino acid sensor of the Rag GTPases and Ragulator complexes, 2 complexes involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:25561175, PubMed:25567906). Following activation by amino acids, the Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. SLC38A9 mediates transport of amino acids with low capacity and specificity with a slight preference for polar amino acids, suggesting that it acts as an amino acid sensor instead (PubMed:25561175, PubMed:25567906). The high concentration of arginine in lysosomes suggests that it acts as an arginine sensor (PubMed:25567906). {ECO:0000269|PubMed:25561175, ECO:0000269|PubMed:25567906}.;
Intolerance Scores
- LoFtool
- 0.749
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 63.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.164
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |