NCSTN

Chr 1AD

nicastrin

Also known as: ATAG1874

NCBI Gene: 23385 ENSG00000162736 UniProt: Q92542 OMIM: 605254

This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014]

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Acne inversa, familial, 1MIM #142690

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Acne inversa, familial; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 0.999

Z-score 5.20

OE 0.10 (0.05–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.43Z-score

OE missense 0.79 (0.72–0.87)

302 obs / 380.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.23)

0≤0.351.4

Missense OE?0.79 (0.72–0.87)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 4 / 39.1Missense obs/exp: 302 / 380.6Syn Z: -0.18

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

808 rare PASS variants

Rare truncating (LoF)

1 in 5,200

56 rare PASS variants

Rare synonymous (reference)

1 in 84

331 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NCSTN. 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 160	1 in 6,800
South Asian	~43k	1 in 75	1 in 6,200
Remaining (unassigned)	~30k	1 in 86	1 in 780
European (Finnish)	~27k	1 in 330	≈ 1 in 13,000
Admixed American	~22k	1 in 85	≈ 1 in 6,600
African / African American	~21k	1 in 78	≈ 1 in 10,000
East Asian	~20k	1 in 80	1 in 2,600
Ashkenazi Jewish	~13k	1 in 580	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 89	none seen

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 17 coding exons well covered in gnomAD exomes and genomes.? see exons ↓