CDH8

Chr 16

cadherin 8

Also known as: Nbla04261

NCBI Gene: 1006 ENSG00000150394 UniProt: P55286 OMIM: 603008

This protein is a type II cadherin that mediates calcium-dependent cell-cell adhesion in the brain and is involved in synaptic adhesion, axon outgrowth and guidance. Mutations cause autosomal dominant neurodevelopmental disorders including developmental and epileptic encephalopathy and autism spectrum disorder. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.30), indicating that even single functional copies may be insufficient for normal brain development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. The extracellular domain consists of 5 subdomains, each containing a cadherin motif, and appears to determine the specificity of the protein's homophilic cell adhesion activity. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. This particular cadherin is expressed in brain and is putatively involved in synaptic adhesion, axon outgrowth and guidance. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.29

Clinical Summary— CDH8

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

76 VUS of 94 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.988

Z-score 4.49

OE 0.13 (0.06–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.42Z-score

OE missense 0.68 (0.62–0.75)

315 obs / 461.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.29)

0≤0.351.4

Missense OE?0.68 (0.62–0.75)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 4 / 31.0Missense obs/exp: 315 / 461.2Syn Z: -0.59

This gene — mechanism propensity

0.6065th %ile

GOF

0.6541th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.29

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

ClinVar Variant Classifications

94 submitted variants in ClinVar

ClinVar

Classification Summary

VUS76

Likely Benign8

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	2	74	0	76
Likely Benign	0	2	6	8
Benign	0	0	2	2
Total	2	76	8	86

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap CDH8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →