NPC2

Chr 14AR

NPC intracellular cholesterol transporter 2

Also known as: EDDM1, HE1

NCBI Gene: 10577ENSG00000119655UniProt: P61916

This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Niemann-pick disease, type C2MIM #607625
AR
Niemann-pick disease, type C2MIM #607625
AR
327
ClinVar variants
75
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NPC2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
75 Pathogenic / Likely Pathogenic· 72 VUS of 327 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.39LOEUF
pLI 0.002
Z-score 0.85
OE 0.67 (0.35–1.39)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.30Z-score
OE missense 0.59 (0.47–0.75)
47 obs / 79.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.67 (0.35–1.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.47–0.75)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.23
0≤1.21.6
LoF obs/exp: 5 / 7.5Missense obs/exp: 47 / 79.7Syn Z: -1.00

ClinVar Variant Classifications

327 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic36
VUS72
Likely Benign151
Benign6
Conflicting14
39
Pathogenic
36
Likely Pathogenic
72
VUS
151
Likely Benign
6
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
6
23
0
39
Likely Pathogenic
15
5
16
0
36
VUS
2
56
14
0
72
Likely Benign
0
10
66
75
151
Benign
0
0
6
0
6
Conflicting
—14
Total277712575318

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NPC2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NPC2-related Niemann-Pick disease

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Niemann-pick disease, type C2

MIM #607625

Molecular basis of disorder known

Autosomal recessive

Niemann-pick disease, type C2

MIM #607625

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Niemann-Pick disease type C.
Vanier MT·Orphanet J Rare Dis
2010Review
Large-Scale Plasma Proteomics Improves Prediction of Peripheral Artery Disease in Individuals With Type 2 Diabetes: A Prospective Cohort Study.
Yu H et al.·Diabetes Care
2025Cohort
The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann-Pick Disease: A Comprehensive Review.
Tirelli C et al.·Biomolecules
2024Review
The characteristics and biological significance of NPC2: Mutation and disease.
Xu Y et al.·Mutat Res Rev Mutat Res
2019Review
Early plasma proteomic biomarkers and prediction model of acute respiratory distress syndrome after cardiopulmonary bypass: a prospective nested cohort study.
Wang Y et al.·Int J Surg
2023Cohort
Niemann-Pick diseases.
Vanier MT·Handb Clin Neurol
2013Review
Structure and function of the NPC2 protein.
Vanier MT et al.·Biochim Biophys Acta
2004Review
Niemann-Pick disease type C.
Vanier MT et al.·Clin Genet
2003Review
Overview of clinical, molecular, and therapeutic features of Niemann-Pick disease (types A, B, and C): Focus on therapeutic approaches.
Hosseini K et al.·Cell Biochem Funct
2024Review
Identification and Classification of Rare Variants in NPC1 and NPC2 in Quebec.
Touma L et al.·Sci Rep
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Multi-omics integration and machine learning identify NPC2 as a prognostic and treatment-responsive regulator in lung adenocarcinoma.
Li A et al.·Front Immunol
2025🔓 Open Access
Interaction between expression of CD23 on B-lymphocytes and level of specific IgE against molecular components of NPC2 family, lipocalins, uteroglobins, and molecular components of molds and yeast.
Čelakovská J et al.·J Immunotoxicol
2025
Functional Analysis of NPC2 in Alarm Pheromone Recognition by the Red Imported Fire Ant, Solenopsis invicta (Formicidae: Solenopsis).
Lin P et al.·Insects
2025🔓 Open AccessFunctional
ALKBH5-mediated NPC2 mRNA m6A demethylation promotes resistance to oxaliplatin in colorectal cancer.
Wan P et al.·Funct Integr Genomics
2025🔓 Open Access
Genome-Wide Identification, Gene Duplication, and Expression Pattern of NPC2 Gene Family in Parnassius glacialis.
Zhu Z et al.·Genes (Basel)
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools