NPC1L1
protein-codingNPC1 like intracellular cholesterol transporter 1, the group of Solute carrier family 65, NPC-type cholesterol transporters
Gene summary
The protein encoded by this gene is a multi-pass membrane protein. It contains a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif functioning as a plasma membrane to trans-Golgi network transport signal in other proteins. This protein takes up free cholesterol into cells through vesicular endocytosis and plays a critical role in the absorption of intestinal cholesterol. It also has the ability to transport alpha-tocopherol (vitamin E). The drug ezetimibe targets this protein and inhibits the absorption of intestinal cholesterol and alpha-tocopherol. In addition, this protein may play a critical role in regulating lipid metabolism. Polymorphic variations in this gene are associated with plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) risk. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
Clinical Genomic Database (CGD)
Manifestation: General
Intervention: Pharmacogenomic
Rationale: Variants may have pharmacogenomic relevance and medication selection may be affected in patients with variants
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPC1L1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001101648.2. 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 | 5 | 24 | 2 | 31 | ||
| missense | 185 | 18 | 7 | 210 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 191 | 42 | 9 | 242 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001095118.1 | 19 | MANE Select | |
| Ensembl | ENSP00000370552.3 | 19 | MANE Select | |
| RefSeq | NP_001287896.1 | 7 | Standard | |
| RefSeq | NP_037521.2 | 20 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fat digestion and absorption - Homo sapiens (human)
- Vitamin A and Carotenoid Metabolism
- C21-steroid hormone biosynthesis and metabolism
- Intestinal lipid absorption
- Intestinal absorption
Biological Process
- cholesterol biosynthetic process
- intestinal cholesterol absorption
- cholesterol transport
- lipoprotein metabolic process
- response to drug
Molecular Function
- protein binding
- drug binding
- Rab GTPase binding
- myosin V binding
Cellular Component
- plasma membrane
- apical plasma membrane
- cytoplasmic vesicle membrane
- brush border membrane
- spanning component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000289547
- Coding exons
- 20
- Length
- 28781
- Individuals with no LoFs
- 125488
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 260
- Defined
- 125748
- p
- 0.00103
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.409 | 729 | 761 | 0.958 | 0.0000484 | 8765 |
| Missense (PolyPhen) | 203 | 234.21 | 0.86676 | 2817 | ||
| Synonymous | -1.44 | 370 | 336 | 1.10 | 0.0000222 | 2903 |
| Loss of Function | 1.94 | 39 | 54.4 | 0.716 | 0.00000309 | 579 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0010 | 0.0010 | notable |
| Latino/Admixed American | 0.00090 | 0.00090 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0067 | 0.0067 | notable |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00064 | 0.00063 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down- regulates its expression and secretion by inhibiting its maturation and accelerating its degradation. {ECO:0000269|PubMed:15928087, ECO:0000269|PubMed:22095670}.;
Recessive Scores
- pRec
- 0.187
Intolerance Scores
- LoFtool
- 0.0150
- RVIS EVS
- 1.38
- RVIS percentile EVS
- 94.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.319
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |