NPC2

Chr 14AR

NPC intracellular cholesterol transporter 2

Also known as: EDDM1, HE1

NCBI Gene: 10577 ENSG00000119655 UniProt: P61916 OMIM: 607625

The protein functions as an intracellular cholesterol transporter that works with NPC1 to facilitate cholesterol egress from the lysosomal compartment by transferring unesterified cholesterol from late endosomes/lysosomes to the cholesterol-binding domain of NPC1. Mutations cause Niemann-Pick disease type C2 through an autosomal recessive inheritance pattern, with disease resulting from loss of cholesterol transport function leading to lysosomal cholesterol accumulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.392 OMIM phenotypes

Clinical Summary— NPC2

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Gene-Disease Validity (ClinGen)

Niemann-Pick disease, type C2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

63 unique Pathogenic / Likely Pathogenic· 69 VUS of 312 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NPC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

1.30Z-score

OE missense 0.59 (0.47–0.75)

47 obs / 79.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.35–1.39)

0≤0.351.4

Missense OE?0.59 (0.47–0.75)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 5 / 7.5Missense obs/exp: 47 / 79.7Syn Z: -1.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNPC2-related Niemann-Pick diseaseLOFAR

Mechanism Note (expert annotation)

LOF

Cholesterol-binding protein in late endosomes/lysosomes. Biallelic LOF causes Niemann-Pick disease type C2. This is a classic autosomal recessive LOF gene; the DN prediction is incorrect.1

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6649th %ile

GOF

0.4677th %ile

LOF

0.3162th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 10617473 ↗

ClinVar Variant Classifications

312 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic34

VUS69

Likely Benign151

Benign6

Conflicting14

Pathogenic

Likely Pathogenic

VUS

151

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	6	4	0	29
Likely Pathogenic	28	5	1	0	34
VUS	3	55	11	0	69
Likely Benign	0	10	66	75	151
Benign	0	0	6	0	6
Conflicting	—				14
Total	50	76	88	75	303

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap NPC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →