CPLX1

Chr 4AR

complexin 1

Also known as: CPX-I, CPX1, DEE63, EIEE63

NCBI Gene: 10815 ENSG00000168993 UniProt: O14810 OMIM: 605032

The protein binds to the SNAP receptor complex and disrupts it to allow neurotransmitter release from synaptic vesicles. Biallelic mutations cause developmental and epileptic encephalopathy 63, inherited in an autosomal recessive pattern. Loss-of-function mutations likely disrupt synaptic transmission by impairing neurotransmitter release.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Proteins encoded by the complexin/synaphin gene family are cytosolic proteins that function in synaptic vesicle exocytosis. These proteins bind syntaxin, part of the SNAP receptor. The protein product of this gene binds to the SNAP receptor complex and disrupts it, allowing transmitter release. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.521 OMIM phenotype

Clinical Summary— CPLX1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.82) — some intolerance to loss-of-function variants.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 42 VUS of 89 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 0.825

Z-score 2.22

OE 0.00 (0.00–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.35Z-score

OE missense 1.11 (0.94–1.32)

93 obs / 83.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.52)

0≤0.351.4

Missense OE?1.11 (0.94–1.32)

0≤0.61.4

Synonymous OE?1.42

0≤1.21.6

LoF obs/exp: 0 / 5.7Missense obs/exp: 93 / 83.9Syn Z: -1.98

This gene — mechanism propensity

0.6261th %ile

GOF

0.6931th %ile

LOF

0.51top 25%

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

89 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3

VUS42

Likely Benign35

Benign3

Conflicting1

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

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	3	0	0	0	3
VUS	1	38	3	0	42
Likely Benign	0	1	14	20	35
Benign	0	0	3	0	3
Conflicting	—				1
Total	4	39	20	20	84

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

View in ClinVar →

148 pathogenic / likely-pathogenic (of 172) ClinVar copy-number / structural variants overlap CPLX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →