CNTN6

Chr 3

contactin 6

Also known as: NB3

NCBI Gene: 27255ENSG00000134115UniProt: Q9UQ52

The protein is a GPI-anchored neuronal membrane glycoprotein that mediates cell surface interactions during nervous system development and participates in oligodendrocyte generation by acting as a NOTCH1 ligand. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy with seizures, developmental delay, and motor coordination problems. This gene has a GeneReviews entry, indicating established clinical significance in pediatric neurology.

Summary from RefSeq, UniProt
Research Assistant →
1
Active trials
6
Pubs (1 yr)
78
P/LP submissions
0%
P/LP missense
1.15
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— CNTN6
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
78 unique Pathogenic / Likely Pathogenic· 355 VUS of 500 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CNTN6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.15LOEUF
pLI 0.000
Z-score 0.62
OE 0.91 (0.72–1.15)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-3.00Z-score
OE missense 1.36 (1.28–1.45)
735 obs / 538.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.91 (0.72–1.15)
0≤0.351.4
Missense OE1.36 (1.28–1.45)
0≤0.61.4
Synonymous OE1.33
0≤1.21.6
LoF obs/exp: 49 / 53.9Missense obs/exp: 735 / 538.7Syn Z: -3.62
DN
0.6745th %ile
GOF
0.6443th %ile
LOF
0.4135th %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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic16
VUS355
Likely Benign29
Benign22
62
Pathogenic
16
Likely Pathogenic
355
VUS
29
Likely Benign
22
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
62
0
62
Likely Pathogenic
1
0
15
0
16
VUS
2
179
174
0
355
Likely Benign
0
9
12
8
29
Benign
0
6
8
8
22
Total319427116484

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

View in ClinVar →

Protein Context — Lollipop Plot

CNTN6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Targeted correction of megabase-scale CNTN6 duplication in induced pluripotent stem cells and impacts on gene expression.
Gridina M et al.·PeerJ
2025Open Access
Familial Psychosis Associated With a Missense Mutation at MACF1 Gene Combined With the Rare Duplications DUP3p26.3 and DUP16q23.3, Affecting the CNTN6 and CDH13 Genes.
Pol-Fuster J et al.·Front Genet
2021Open Access
Generation of four iPSC lines from two siblings with a microdeletion at the CNTN6 gene and intellectual disability.
Shnaider TA et al.·Stem Cell Res
2019
Time origin and structural analysis of the induced CRISPR/cas9 megabase-sized deletions and duplications involving the Cntn6 gene in mice.
Pristyazhnyuk IE et al.·Sci Rep
2019Open Access
Generation of the induced pluripotent stem cell line, ICAGi002-A, from unaffected carrier megabase scaled duplication involving the CNTN6 gene.
Gridina MM et al.·Stem Cell Res
2019
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients