PACS1

Chr 11AD

phosphofurin acidic cluster sorting protein 1

Also known as: MRD17, SHMS

NCBI Gene: 55690 ENSG00000175115 UniProt: Q6VY07 OMIM: 607492

The protein localizes trans-Golgi network membrane proteins by binding to phosphorylated cytosolic domains of target proteins like furin. Mutations cause Schuurs-Hoeijmakers syndrome through an autosomal dominant inheritance pattern. The pathogenic mechanism involves loss of function, which is consistent with the protein's critical role in Golgi trafficking.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOFmechanismADLOEUF 0.181 OMIM phenotype

Clinical Summary— PACS1

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Gene-Disease Validity (ClinGen)

Schuurs-Hoeijmakers syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.18LOEUF

pLI 1.000

Z-score 5.99

OE 0.08 (0.04–0.18)

Highly constrained

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

Missense Constraint

3.71Z-score

OE missense 0.55 (0.50–0.61)

302 obs / 545.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.08 (0.04–0.18)

0≤0.351.4

Missense OE0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE0.87

0≤1.21.6

LoF obs/exp: 4 / 49.4Missense obs/exp: 302 / 545.9Syn Z: 1.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePACS1-related intellectual disabilityGOFAD

0.4190th %ile

GOF

0.3689th %ile

LOF

0.80top 5%

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

LOFprediction above median · LOEUF 0.18

DN1 literature citation

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.

Literature Evidence

DNFurthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion.PMID:23159249

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