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…

Primary Disease Associations & Inheritance

Niemann-pick disease, type C2MIM #607625

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Niemann-Pick disease, type C2 · AR · ClinGen 2022
Supportive · Niemann-Pick disease type C, severe perinatal form · AR · Orphanet
Supportive · Niemann-Pick disease type C, severe early infantile neurologic onset · AR · Orphanet
Supportive · Niemann-Pick disease type C, late infantile neurologic onset · AR · Orphanet

+2 more curated pairs

Interpreting a novel variant

Loss of function is the established mechanism, though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

108

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.39

LOEUF

LOF

Mechanism· annotated

📖

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

Background carrier burden — how many people carry a rare variant somewhere in NPC2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

416 rare PASS variants

Rare truncating (LoF)

1 in 1,000

79 rare PASS variants

Rare synonymous (reference)

1 in 320

179 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NPC2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 1,800
South Asian	~43k	1 in 100	1 in 560
Remaining (unassigned)	~30k	1 in 85	1 in 780
European (Finnish)	~27k	1 in 1,400	≈ 1 in 8,300
Admixed American	~22k	1 in 120	1 in 1,600
African / African American	~21k	1 in 170	1 in 220
East Asian	~20k	1 in 170	1 in 1,500
Ashkenazi Jewish	~13k	≈ 1 in 6,500	none seen
Middle Eastern	~2,884	1 in 120	1 in 480

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓