PACS2

Chr 14AD

phosphofurin acidic cluster sorting protein 2

Also known as: DEE66, EIEE66, PACS-2, PACS1L

NCBI Gene: 23241ENSG00000179364UniProt: Q86VP3

Predicted to enable transmembrane transporter binding activity. Involved in endoplasmic reticulum calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and protein localization to plasma membrane. Acts upstream of or within protein localization to phagophore assembly site. Located in endoplasmic reticulum and mitochondrion. Implicated in developmental and epileptic encephalopathy 66. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 66MIM #618067
AD
583
ClinVar variants
9
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— PACS2
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · 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
9 Pathogenic / Likely Pathogenic· 270 VUS of 583 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
LoF intolerant — likely haploinsufficient
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.
0.28LOEUF
pLI 0.996
Z-score 5.41
OE 0.15 (0.08–0.28)
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.
2.24Z-score
OE missense 0.73 (0.68–0.80)
414 obs / 563.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.15 (0.08–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.68–0.80)
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.1.11
0≤1.21.6
LoF obs/exp: 7 / 47.1Missense obs/exp: 414 / 563.3Syn Z: -1.41

ClinVar Variant Classifications

583 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
VUS270
Likely Benign260
Benign32
Conflicting12
9
Pathogenic
270
VUS
260
Likely Benign
32
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
0
0
0
VUS
10
218
35
7
270
Likely Benign
0
23
105
132
260
Benign
0
21
7
4
32
Conflicting
—12
Total10262156143583

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

View in ClinVar →

Protein Context — Lollipop Plot

PACS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PACS2-related neurodevelopmental disorder

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 66

MIM #618067

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop.
Ouyang J et al.·Biochem Pharmacol
2025
Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature.
Stoian A et al.·Biomolecules
2024Review
Expanding the clinical spectrum associated with PACS2 mutations.
Dentici ML et al.·Clin Genet
2019Review
First reported case of an inherited PACS2 pathogenic variant with variable expression.
Cesaroni E et al.·Epileptic Disord
2022Case report
PACS2 pathogenic variant associated with malformation of cortical development and epilepsy.
Checri R et al.·Epileptic Disord
2024Case report
In conversation with Małgorzata Kosla.
Kosla M et al.·FEBS J
2025
Vein of Galen aneurysm, dilated cardiomyopathy, and slender habitus in a patient with a recurrent pathogenic variant in PACS2.
Valenzuela I et al.·Am J Med Genet A
2022Case report
[Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review].
Wu MJ et al.·Zhonghua Er Ke Za Zhi
2021Review
PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype in Drosophila melanogaster.
Frappaolo A et al.·Open Biol
2025
Clinical variations of epileptic syndrome associated with PACS2 variant.
Mizuno T et al.·Brain Dev
2021Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Quercetin Alleviates Endothelial Dysfunction in Atherosclerosis by Inhibiting Ferroptosis Through PACS2/HMOX-1 Pathway.
Long HJ et al.·Am J Chin Med
2026
PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice.
Zou H et al.·Biochem Pharmacol
2026
MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress.
Chen R et al.·J Cardiovasc Transl Res
2026🔓 Open Access
AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes.
Del Rincón J et al.·Int J Mol Sci
2025🔓 Open Access
PACS2/PKCα/NOX4 pathway damaged the renal vascular endothelial barrier by promoting ROS production in diabetic nephropathy mice.
Zheng X et al.·Mol Cell Biochem
2025
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