CPNE3

Chr 8

copine 3

Also known as: CPN3, PRO1071

NCBI Gene: 8895 ENSG00000085719 UniProt: O75131

CPNE3 encodes a calcium-dependent phospholipid-binding protein that contains C2 domains for membrane binding and facilitates cell migration through ERBB2-mediated pathways. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, seizures, and movement abnormalities. The gene shows minimal constraint against loss-of-function mutations, consistent with recessive inheritance patterns.

Summary from RefSeq, UniProt

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Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

1.54

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— CPNE3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 72 VUS of 140 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.54LOEUF

pLI 0.000

Z-score -0.82

OE 1.16 (0.89–1.54)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.98Z-score

OE missense 1.16 (1.06–1.27)

329 obs / 282.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE1.16 (0.89–1.54)

0≤0.351.4

Missense OE1.16 (1.06–1.27)

0≤0.61.4

Synonymous OE0.98

0≤1.21.6

LoF obs/exp: 35 / 30.1Missense obs/exp: 329 / 282.8Syn Z: 0.16

0.6745th %ile

GOF

0.7127th %ile

LOF

0.3843th %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.