PCDH9

Chr 13

protocadherin 9

NCBI Gene: 5101 ENSG00000184226 UniProt: Q9HC56

This gene encodes protocadherin-9, a calcium-dependent cell adhesion protein that mediates cell adhesion in neural tissues and may function in signaling at neuronal synaptic junctions. Mutations cause neurodevelopmental disorders with intellectual disability, and the gene shows autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, reflecting its critical role in nervous system development and function.

GeneReviews ResearchSummary from RefSeq, UniProt

This gene encodes a member of the protocadherin family, and cadherin superfamily, of transmembrane proteins containing cadherin domains. These proteins mediate cell adhesion in neural tissues in the presence of calcium. The encoded protein may be involved in signaling at neuronal synaptic junctions. Sharing a characteristic with other protocadherin genes, this gene has a notably large exon that encodes multiple cadherin domains and a transmembrane region. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

GeneReviews ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.37

LOEUF

—

Mechanism

📖

GeneReview available — PCDH9

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.809

Z-score 4.25

OE 0.19 (0.10–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.33Z-score

OE missense 0.75 (0.69–0.80)

495 obs / 663.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.37)

0≤0.351.4

Missense OE?0.75 (0.69–0.80)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 6 / 31.9Missense obs/exp: 495 / 663.9Syn Z: -0.34

Background carrier burden — how many people carry a rare variant somewhere in PCDH9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 42

1,403 rare PASS variants

Rare truncating (LoF)

1 in 5,800

51 rare PASS variants

Rare synonymous (reference)

1 in 84

596 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PCDH9. 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 76	1 in 6,700
South Asian	~43k	1 in 58	≈ 1 in 22,000
Remaining (unassigned)	~30k	1 in 52	≈ 1 in 15,000
European (Finnish)	~27k	1 in 170	1 in 3,800
Admixed American	~22k	1 in 62	none seen
African / African American	~21k	1 in 61	≈ 1 in 4,900
East Asian	~20k	1 in 57	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 150	none seen
Middle Eastern	~2,884	1 in 57	≈ 1 in 1,100

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): 2 of 4 coding exons well covered in gnomAD exomes; exons 3, 4 marginal. Genomes: all 4.? see exons ↓