PCDHGC4

Chr 5

protocadherin gamma subfamily C, 4

Also known as: NEDGS, PCDH-GAMMA-C4

NCBI Gene: 56098 ENSG00000242419 UniProt: Q9Y5F7

This gene encodes a neural protocadherin that functions as a calcium-dependent cell adhesion protein involved in establishing and maintaining specific neuronal connections in the brain. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with poor growth and skeletal anomalies. The gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.31), indicating intolerance to protein-disrupting mutations.

ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.31

Clinical Summary— PCDHGC4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.980

Z-score 4.36

OE 0.14 (0.07–0.31)

Highly constrained

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

Missense Constraint?

1.97Z-score

OE missense 0.76 (0.70–0.83)

422 obs / 552.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.31)

0≤0.351.4

Missense OE?0.76 (0.70–0.83)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 4 / 29.6Missense obs/exp: 422 / 552.1Syn Z: 2.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPCDHGC4-related neurodevelopmental disorder with microcephaly and seizuresOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6454th %ile

GOF

0.6443th %ile

LOF

0.57top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.