PACS1

Chr 11AD

phosphofurin acidic cluster sorting protein 1

Also known as: MRD17, SHMS

NCBI Gene: 55690ENSG00000175115UniProt: Q6VY07

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]

Primary Disease Associations & Inheritance

Schuurs-Hoeijmakers syndromeMIM #615009
AD
575
ClinVar variants
3
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— PACS1
🧬
Gene-Disease Validity (ClinGen)
Schuurs-Hoeijmakers syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
3 Pathogenic / Likely Pathogenic· 265 VUS of 575 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.04–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.50–0.61)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.87
0≤1.21.6
LoF obs/exp: 4 / 49.4Missense obs/exp: 302 / 545.9Syn Z: 1.48

ClinVar Variant Classifications

575 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic2
VUS265
Likely Benign272
Benign23
Conflicting12
1
Pathogenic
2
Likely Pathogenic
265
VUS
272
Likely Benign
23
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
0
1
1
0
2
VUS
17
216
30
2
265
Likely Benign
1
17
146
108
272
Benign
0
16
6
1
23
Conflicting
—12
Total18250184111575

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

View in ClinVar →

Protein Context — Lollipop Plot

PACS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PACS1-related intellectual disability

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Schuurs-Hoeijmakers syndrome

MIM #615009

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — PACS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing.
Bruno LP et al.·Int J Mol Sci
2021Clinical trial
Expanding the Clinical Spectrum Associated with the Recurrent Arg203Trp Variant in PACS1: An Italian Cohort Study.
Pagano S et al.·Genes (Basel)
2025Cohort
PACS1-Neurodevelopmental disorder: clinical features and trial readiness.
Van Nuland A et al.·Orphanet J Rare Dis
2021
iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
Rylaarsdam L et al.·Nat Commun
2024Functional
Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?
Moller-Hansen A et al.·Am J Med Genet A
2023Case report
Schuurs-Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review.
Tenorio-Castaño J et al.·Genes (Basel)
2021Review
PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype in Drosophila melanogaster.
Frappaolo A et al.·Open Biol
2025
PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.
Byrd DT et al.·Genetics
2024Functional
Molecular Basis of the Schuurs-Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches.
Arnedo M et al.·Int J Mol Sci
2022Review
PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma in Schuurs-Hoeijmakers syndrome.
Ohkawa T et al.·J Hum Genet
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools