PCDH12

Chr 5AR

protocadherin 12

NCBI Gene: 51294ENSG00000113555UniProt: Q9NPG4

Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions (By similarity). Acts as a regulator of cell migration, probably via increasing cell-cell adhesion (PubMed:21402705). Promotes homotypic calcium-dependent aggregation and adhesion and clusters at intercellular junctions (By similarity). Unable to bind to catenins, weakly associates with the cytoskeleton (By similarity)

Primary Disease Associations & Inheritance

Diencephalic-mesencephalic junction dysplasia syndrome 1MIM #251280
AR
394
ClinVar variants
19
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PCDH12
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
19 Pathogenic / Likely Pathogenic· 211 VUS of 394 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.98LOEUF
pLI 0.000
Z-score 1.65
OE 0.70 (0.51–0.98)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.78Z-score
OE missense 0.92 (0.86–0.98)
622 obs / 679.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.70 (0.51–0.98)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.86–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 25 / 35.6Missense obs/exp: 622 / 679.5Syn Z: 1.02

ClinVar Variant Classifications

394 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic13
VUS211
Likely Benign131
Benign12
Conflicting21
6
Pathogenic
13
Likely Pathogenic
211
VUS
131
Likely Benign
12
Benign
21
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
3
0
6
Likely Pathogenic
5
2
6
0
13
VUS
1
202
8
0
211
Likely Benign
0
18
6
107
131
Benign
0
8
0
4
12
Conflicting
—21
Total923023111394

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

View in ClinVar →

Protein Context — Lollipop Plot

PCDH12 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PCDH12-related diencephalic-mesencephalic junction dysplasia syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
PROTOCADHERIN 12; PCDH12
MIM #605622 · *

Diencephalic-mesencephalic junction dysplasia syndrome 1

MIM #251280

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The phenotypic spectrum of PCDH12 associated disorders - Five new cases and review of the literature.
Fazeli W et al.·Eur J Paediatr Neurol
2022Review
Expanding spectrum of PCDH12 related phenotype begs exploration of multipronged pathomechanisms.
Aggarwal S·Eur J Paediatr Neurol
2022Functional
Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.
Guemez-Gamboa A et al.·Ann Neurol
2018
PCDH12 variants are associated with basal ganglia anomalies and exudative vitreoretinopathy.
Accogli A et al.·Eur J Med Genet
2022Case report
Asynchronous presentation and evolution of homozygous PCDH12 variant-induced exudative retinopathy in two siblings.
Youn EY et al.·Can J Ophthalmol
2023Case report
Proteomics-Based Analysis of Clinical Significance of Roundabout Guidance Receptor 4 and Protocadherin 12 in Screening,Diagnosis,and Staging of Colorectal Cancer.
Fan JC et al.·Zhongguo Yi Xue Ke Xue Yuan Xue Bao
2025
Homozygous PCDH12 variants result in phenotype of cerebellar ataxia, dystonia, retinopathy, and dysmorphism.
Vineeth VS et al.·J Hum Genet
2019Case report
Ophthalmic phenotypes associated with biallelic loss-of-function PCDH12 variants.
Mattioli F et al.·Am J Med Genet A
2021Case report
Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection.
Aran A et al.·Neurology
2016
SMAD6 transduces endothelial cell flow responses required for blood vessel homeostasis.
Ruter DL et al.·Angiogenesis
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools