CADPS

Chr 3

calcium dependent secretion activator

Also known as: CADPS1, CAPS, CAPS1, UNC-31

NCBI Gene: 8618 ENSG00000163618 UniProt: Q9ULU8 OMIM: 604667

The protein functions as a calcium-binding protein that regulates the exocytosis of neurotransmitter-filled vesicles at synapses, acting downstream of ATP-dependent priming to mediate vesicle fusion with cell membranes. Mutations cause autosomal recessive intellectual disability, autism spectrum disorder, and seizures, typically presenting in early childhood. The gene is highly constrained against loss-of-function variants (LOEUF 0.435), indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a novel neural/endocrine-specific cytosolic and peripheral membrane protein required for the Ca2+-regulated exocytosis of secretory vesicles. The protein acts at a stage in exocytosis that follows ATP-dependent priming, which involves the essential synthesis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Alternative splicing has been observed at this locus and three variants, encoding distinct isoforms, are described. [provided by RefSeq, Aug 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.43

Clinical Summary— CADPS

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

144 VUS of 196 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.43LOEUF

pLI 0.000

Z-score 5.64

OE 0.31 (0.22–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.10Z-score

OE missense 0.68 (0.64–0.74)

525 obs / 766.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.31 (0.22–0.43)

0≤0.351.4

Missense OE?0.68 (0.64–0.74)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 24 / 77.6Missense obs/exp: 525 / 766.6Syn Z: -1.44

This gene — mechanism propensity

0.6259th %ile

GOF

0.6834th %ile

LOF

0.4233th %ile

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

GOFprediction above median

DNprediction 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

196 submitted variants in ClinVar

ClinVar

Classification Summary

VUS144

Likely Benign30

Benign5

144

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	3	140	0	1	144
Likely Benign	0	3	4	23	30
Benign	0	0	2	3	5
Total	3	143	6	27	179

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap CADPS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →