CNTN3

Chr 3

contactin 3

Also known as: BIG-1, PANG, PCS

NCBI Gene: 5067 ENSG00000113805 UniProt: Q9P232 OMIM: 601325

The protein mediates cell surface interactions during nervous system development and promotes neurite outgrowth as a cell adhesion molecule located in the extracellular region and plasma membrane. Mutations cause autosomal recessive developmental and epileptic encephalopathy with cortical blindness, intellectual disability, and seizures typically beginning in infancy. The gene shows low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in cell adhesion. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in neuron projection. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.51

Clinical Summary— CNTN3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

121 VUS of 172 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?

0.51LOEUF

pLI 0.000

Z-score 4.37

OE 0.35 (0.24–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.32Z-score

OE missense 0.84 (0.78–0.91)

460 obs / 546.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.24–0.51)

0≤0.351.4

Missense OE?0.84 (0.78–0.91)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 18 / 52.0Missense obs/exp: 460 / 546.8Syn Z: -0.41

This gene — mechanism propensity

0.74top 25%

GOF

0.6541th %ile

LOF

0.3454th %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

172 submitted variants in ClinVar

ClinVar

Classification Summary

VUS121

Likely Benign20

Benign12

121

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	120	1	0	121
Likely Benign	10	3	7	20
Benign	6	3	3	12
Total	136	7	10	153

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap CNTN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →