PCDH8

Chr 13

protocadherin 8

Also known as: ARCADLIN, PAPC

NCBI Gene: 5100 ENSG00000136099 UniProt: O95206

PCDH8 encodes protocadherin-8, a calcium-dependent cell adhesion protein that functions in CNS-specific cell adhesion and may regulate synaptic reorganization and dendritic spine dynamics in hippocampal neurons. Mutations cause autosomal recessive intellectual disability with seizures and language delay. This gene is not highly constrained against loss-of-function variants.

ResearchSummary from RefSeq, UniProt

This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The gene encodes an integral membrane protein that is thought to function in cell adhesion in a CNS-specific manner. Unlike classical cadherins, which are generally encoded by 15-17 exons, this gene includes only 3 exons. Notable is the large first exon encoding the extracellular region, including 6 cadherin domains and a transmembrane region. Alternative splicing yields isoforms with unique cytoplasmic tails. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.26

OE 0.49 (0.30–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.90Z-score

OE missense 0.77 (0.72–0.84)

439 obs / 566.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.30–0.81)

0≤0.351.4

Missense OE?0.77 (0.72–0.84)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 11 / 22.6Missense obs/exp: 439 / 566.5Syn Z: 0.58

Background carrier burden — how many people carry a rare variant somewhere in PCDH8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

1,614 rare PASS variants

Rare truncating (LoF)

1 in 1,900

109 rare PASS variants

Rare synonymous (reference)

1 in 99

837 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PCDH8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 63	1 in 2,600
South Asian	~43k	1 in 47	1 in 460
Remaining (unassigned)	~30k	1 in 50	1 in 6,000
European (Finnish)	~27k	1 in 170	1 in 720
Admixed American	~22k	1 in 42	1 in 2,600
African / African American	~21k	1 in 50	1 in 3,500
East Asian	~20k	1 in 43	1 in 1,600
Ashkenazi Jewish	~13k	1 in 120	1 in 1,200
Middle Eastern	~2,884	1 in 51	≈ 1 in 800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓