CDH15

Chr 16AD

cadherin 15

Also known as: CDH14, CDH3, CDHM, MCAD, MRD3

NCBI Gene: 1013 ENSG00000129910 UniProt: P55291 OMIM: 114019

This gene encodes M-cadherin, a calcium-dependent cell adhesion protein that is essential for myogenesis and provides a trigger for terminal muscle cell differentiation. Mutations cause autosomal dominant intellectual developmental disorder. The gene is highly intolerant to loss-of-function variants, indicating that proper protein function is critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the cadherin superfamily of genes, encoding calcium-dependent intercellular adhesion glycoproteins. Cadherins consist of an extracellular domain containing 5 cadherin domains, a transmembrane region, and a conserved cytoplasmic domain. Transcripts from this particular cadherin are expressed in myoblasts and upregulated in myotubule-forming cells. The protein is thought to be essential for the control of morphogenetic processes, specifically myogenesis, and may provide a trigger for terminal muscle cell differentiation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 1.101 OMIM phenotype

Clinical Summary— CDH15

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Gene-Disease Validity (ClinGen)

intellectual disability · ADDisputed

Disputed — evidence questions this relationship

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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

253 VUS of 387 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 1.09

OE 0.79 (0.58–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.01Z-score

OE missense 1.12 (1.05–1.20)

591 obs / 526.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.79 (0.58–1.10)

0≤0.351.4

Missense OE?1.12 (1.05–1.20)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 25 / 31.6Missense obs/exp: 591 / 526.0Syn Z: -2.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCDH15-related intellectual developmental disorderLOFAD

This gene — mechanism propensity

0.7327th %ile

GOF

0.78top 25%

LOF

0.3454th %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.

ClinVar Variant Classifications

387 submitted variants in ClinVar

ClinVar

Classification Summary

VUS253

Likely Benign95

Benign17

Conflicting16

253

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	11	233	6	3	253
Likely Benign	0	34	8	53	95
Benign	1	7	0	9	17
Conflicting	—				16
Total	12	274	14	65	381

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

View in ClinVar →

72 pathogenic / likely-pathogenic (of 109) ClinVar copy-number / structural variants overlap CDH15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →