PCDHGB1

Chr 5

protocadherin gamma subfamily B, 1

Also known as: PCDH-GAMMA-B1

NCBI Gene: 56104 ENSG00000254221 UniProt: Q9Y5G3

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]

Active trials

Pathogenic / LP

398

ClinVar variants

Pubs (1 yr)

0.1

Missense Z

0.72

LOEUF

Clinical Summary— PCDHGB1

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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

1 Pathogenic / Likely Pathogenic· 352 VUS of 398 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.72LOEUF

pLI 0.000

Z-score 2.63

OE 0.43 (0.27–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.10Z-score

OE missense 0.99 (0.92–1.06)

561 obs / 568.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.43 (0.27–0.72)

0≤0.351.4

Missense OE0.99 (0.92–1.06)

0≤0.61.4

Synonymous OE1.16

0≤1.21.6

LoF obs/exp: 11 / 25.3Missense obs/exp: 561 / 568.0Syn Z: -2.02

DNGOF

Badonyi & Marsh 2024 ↗

0.85top 5%

GOF

0.79top 25%

LOF

0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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.