PACS1

Chr 11

phosphofurin acidic cluster sorting protein 1

Also known as: MRD17, SHMS

NCBI Gene: 55690 ENSG00000175115 UniProt: Q6VY07

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.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.18

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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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 265 VUS of 738 total submissions

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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 →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.08 (0.04–0.18)

0≤0.351.4

Missense OE?0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?0.87

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

This gene — mechanism propensity

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.1

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

References

1.PMID 23159249 ↗

ClinVar Variant Classifications

738 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3

VUS265

Likely Benign317

Benign81

Conflicting47

Likely Pathogenic

265

VUS

317

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	2	0	0	3
VUS	25	222	16	2	265
Likely Benign	1	37	149	130	317
Benign	0	16	62	3	81
Conflicting	—				47
Total	27	277	227	135	713

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PACS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →