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NPC2

NPC intracellular cholesterol transporter 2

The NPC2 gene provides instructions for a protein critical in regulating cholesterol movement within cells, with specific variants linked to Niemann-Pick disease type C2. The NPC2 gene is essential for cellular lipid metabolism, coding for a protein that binds to cholesterol within lysosomes.

Chromosome 14q24.3 Autosomal recessive HGNC:14537 Tier C
NPC2 14q24.3 p arm q arm 14

NPC2 is located on the long (q) arm of chromosome 14, at band 14q24.3. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 14 in the library →

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Clinical tests that include this

Carrier Screening panel
NPC2 is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions

Overview

The NPC2 gene, also known as NPC intracellular cholesterol transporter 2, is crucial for normal cellular function, particularly in the processing and transport of lipids. It provides instructions for making a protein that facilitates the movement of cholesterol and other fats from lysosomes, which are cellular recycling centres, to other parts of the cell [PMID:16000995].

Pathogenic variants in the NPC2 gene are associated with inherited conditions, most notably Niemann-Pick disease type C2, a specific form of Niemann-Pick disease type C.

What the gene does

The protein encoded by the NPC2 gene plays a vital role within lysosomes, specialised compartments in cells responsible for breaking down and recycling waste materials. Specifically, the NPC2 protein is involved in the intracellular transport of cholesterol. It directly binds to cholesterol, helping to move this waxy, fat-like substance out of the lysosomes so it can be utilised by other cellular components.

This function is critical for maintaining cellular lipid homeostasis. When the NPC2 protein is deficient or non-functional due to genetic variants, cholesterol and other lipids can build up abnormally within lysosomes. This accumulation disrupts various cellular processes and can lead to the symptoms observed in associated conditions [PMID:11590432].

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Chromosome location

The NPC2 gene is located on chromosome 14 at position 14q24.3. This specific genomic location helps define the gene's position within the human genome.

Protein structure

The NPC2 protein consists of 151 amino acids.

Key variants

Variants in the NPC2 gene can alter the function of the NPC2 protein, affecting its ability to bind and transport cholesterol. These genetic changes can range from small alterations in DNA sequence to larger deletions or insertions. More than 20 specific genetic variants in the NPC2 gene have been identified and linked to Niemann-Pick disease type C2 [PMID:12389104].

The table below shows the top 10 pathogenic or likely-pathogenic variants currently classified in ClinVar for NPC2.
View all on ClinVar →

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.133C>T
single nucleotide variant
 p.Gln45Ter Pathogenic/Likely pathogenic ★★☆☆ Niemann-Pick disease, type C
c.141C>A
single nucleotide variant
 p.Cys47Ter Pathogenic ★★☆☆ Inborn genetic diseases
c.165C>G
single nucleotide variant
 p.Tyr55Ter Pathogenic ★★☆☆ Niemann-Pick disease, type C2
c.190+5G>A
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ Niemann-Pick disease, type C2
c.210_213dup
Duplication
 p.Ala72fs Pathogenic/Likely pathogenic ★★☆☆ Niemann-Pick disease, type C2
c.279dup
Duplication
 p.Lys94Ter Pathogenic/Likely pathogenic ★★☆☆ Niemann-Pick disease, type C
c.295T>C
single nucleotide variant
 p.Cys99Arg Pathogenic ★★☆☆ Niemann-Pick disease, type C2
c.352G>T
single nucleotide variant
 p.Glu118Ter Pathogenic ★★☆☆ Niemann-Pick disease, type C
c.358C>T
single nucleotide variant
 p.Pro120Ser Pathogenic/Likely pathogenic ★★☆☆ Niemann-Pick disease, type C
c.3G>C
single nucleotide variant
 p.Met1Ile Pathogenic/Likely pathogenic ★★☆☆ Niemann-Pick disease, type C

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Variants in the NPC2 gene are known to cause Niemann-Pick disease type C2. This is an inherited condition characterised by the abnormal accumulation of fatty substances within cells, particularly cholesterol. This build-up of fat can lead to a range of symptoms, including neurological impairment, movement problems, speech and feeding difficulties, and issues affecting the liver and lungs.

Inheritance pattern

Conditions caused by pathogenic NPC2 variants typically follow autosomal recessive inheritance.

♀ Carrier parent 1 altered copy ♂ Carrier parent 1 altered copy Affected Carrier Carrier Unaffected Affected Carrier Unaffected Circles = females · Squares = males

When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.

Carrier frequency by population How common is heterozygous NPC2 carrier status across ancestry groups?

UK clinical status

The NPC2 gene is included in several NHS Genomic Medicine Service (GMS) approved clinical panels. These panels cover a range of conditions including Ataxia and cerebellar anomalies - childhood onset, Cholestasis, Dystonia, chorea or related movement disorder, childhood onset, Foetal anomalies, Hereditary ataxia, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Neonatal cholestasis, Neurodegenerative disorders, adult onset, Niemann Pick disease type C, and Undiagnosed metabolic disorders, indicating its recognised clinical significance in the UK.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Cholestasis · R171 NHS GMS → Dystonia, chorea or related movement disorder, childhood onset · R57 NHS GMS → Fetal anomalies · R21 NHS GMS → Likely inborn error of metabolism · R98 NHS GMS → Lysosomal storage disorder · R276 NHS GMS → Niemann Pick disease type C · R380 NHS GMS → Ataxia and cerebellar anomalies - childhood onset NHS GMS → DDG2P NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the main function of the NPC2 gene?

The NPC2 gene provides instructions for a protein that plays a crucial role in the movement of cholesterol out of lysosomes within cells. It binds to cholesterol, facilitating its transport to other parts of the cell for use or further processing.

What condition is associated with variants in the NPC2 gene?

Variants in the NPC2 gene are primarily associated with Niemann-Pick disease type C2. This condition involves the abnormal accumulation of lipids, particularly cholesterol, within cells, leading to a range of symptoms affecting neurological and other body systems.

How is Niemann-Pick disease type C2 inherited?

Niemann-Pick disease type C2, caused by NPC2 variants, is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.

References

  1. Patterson MC, Mengel E, Wijburg FA. Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet journal of rare diseases. 2013. PMID: 23324478
  2. Mengel E, Klünemann HH, Lourenço CM. Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet journal of rare diseases. 2013. PMID: 24135395
  3. Verot L, Chikh K, Freydière E. Niemann-Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clinical genetics. 2007. PMID: 17470133
  4. Xu S, Benoff B, Liou HL. Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease. The Journal of biological chemistry. 2007. PMID: 17573352
  5. Vanier MT, Millat G. Structure and function of the NPC2 protein. Biochimica et biophysica acta. 2004. PMID: 15465422
  6. Sturley SL, Patterson MC, Balch W. The pathophysiology and mechanisms of NP-C disease. Biochimica et biophysica acta. 2004. PMID: 15465429
  7. Chikh K, Vey S, Simonot C. Niemann-Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Molecular genetics and metabolism. 2004. PMID: 15542393
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 4 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .