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…

LOFmechanismADLOEUF 0.231 OMIM phenotype

Clinical Summary— NCSTN

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 188 VUS of 396 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.3594th %ile

GOF

0.4972th %ile

LOF

0.55top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 100% of P/LP variants are LoF · LOEUF 0.23

Literature Evidence

LOFWang et al. (2010) identified 3 families of Han Chinese origin segregating autosomal dominant familial acne inversa (ACNINV1; 142690) due to mutation in the NCSTN gene (605254.0001-605254.0003). All 3 of the mutations led to haploinsufficiency.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 20929727 ↗

ClinVar Variant Classifications

396 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic6

VUS188

Likely Benign158

Benign17

Conflicting4

Pathogenic

Likely Pathogenic

188

VUS

158

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	6	0	0	0	6
VUS	1	168	14	5	188
Likely Benign	0	2	83	73	158
Benign	0	1	7	9	17
Conflicting	—				4
Total	10	171	104	87	376

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

View in ClinVar →

3 pathogenic / likely-pathogenic (of 4) ClinVar copy-number / structural variants overlap NCSTN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →