CNTN2

Chr 1AR

contactin 2

Also known as: AXT, EPEO5, FAME5, TAG-1, TAX, TAX1

NCBI Gene: 6900 ENSG00000184144 UniProt: Q02246 OMIM: 190197

This protein is a GPI-anchored neuronal membrane glycoprotein that organizes axonal domains at nodes of Ranvier by maintaining voltage-gated potassium channels at the juxtaparanodal region and functions in neuronal proliferation, migration, and axon guidance during cerebellar development. Autosomal recessive mutations cause early-onset epilepsy with or without developmental delay. The gene is highly constrained against loss-of-function variants (LOEUF 0.437), indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.441 OMIM phenotype

Clinical Summary— CNTN2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 228 VUS of 584 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?

0.44LOEUF

pLI 0.002

Z-score 4.92

OE 0.29 (0.19–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.59Z-score

OE missense 0.72 (0.67–0.78)

481 obs / 669.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.29 (0.19–0.44)

0≤0.351.4

Missense OE?0.72 (0.67–0.78)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 16 / 55.6Missense obs/exp: 481 / 669.4Syn Z: 1.02

This gene — mechanism propensity

0.76top 25%

GOF

0.6639th %ile

LOF

0.3550th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-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

LOF94% of P/LP variants are LoF · LOEUF 0.44

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

584 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic13

VUS228

Likely Benign286

Benign17

Conflicting16

Pathogenic

Likely Pathogenic

228

VUS

286

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	0	1	0	20
Likely Pathogenic	12	0	1	0	13
VUS	1	211	13	3	228
Likely Benign	0	9	106	171	286
Benign	0	5	2	10	17
Conflicting	—				16
Total	32	225	123	184	580

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap CNTN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →