NCS1

Chr 9

neuronal calcium sensor 1

Also known as: FLUP, FREQ

NCBI Gene: 23413ENSG00000107130UniProt: P62166OMIM: 603315

The protein functions as a neuronal calcium sensor that regulates G protein-coupled receptor phosphorylation in a calcium-dependent manner and modulates synaptic transmission and plasticity. Mutations in NCS1 cause autosomal dominant neurodegeneration through a predicted gain-of-function mechanism. The protein directly regulates rhodopsin kinase (GRK1) and stimulates phosphatidylinositol 4-kinase activity, with disruption leading to progressive neuronal dysfunction.

OMIMResearchSummary from RefSeq, UniProt, Mechanism
MultiplemechanismLOEUF 0.52
Clinical Summary— NCS1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.66) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
31 unique Pathogenic / Likely Pathogenic· 19 VUS of 64 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.52LOEUF
pLI 0.664
Z-score 2.71
OE 0.16 (0.07–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.22Z-score
OE missense 0.40 (0.31–0.51)
43 obs / 107.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.16 (0.07–0.52)
0≤0.351.4
Missense OE0.40 (0.31–0.51)
0≤0.61.4
Synonymous OE0.82
0≤1.21.6
LoF obs/exp: 2 / 12.2Missense obs/exp: 43 / 107.8Syn Z: 0.97
DN
0.74top 25%
GOF
0.73top 25%
LOF
0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

64 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic2
VUS19
Likely Benign1
Benign2
29
Pathogenic
2
Likely Pathogenic
19
VUS
1
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
29
0
29
Likely Pathogenic
0
0
2
0
2
VUS
0
9
10
0
19
Likely Benign
0
0
0
1
1
Benign
0
0
2
0
2
Total0943153

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

View in ClinVar →

Protein Context — Lollipop Plot

NCS1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients