PACS2
protein-codingphosphofurin acidic cluster sorting protein 2
Gene summary
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. Implicated in developmental and epileptic encephalopathy 66. [provided by Alliance of Genome Resources, Jun 2026]
- PACS1L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~97.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0054845
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0054845
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0054845
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: ClinGen
*PACS2* was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2018 (Olsen et al., PMID: 29656858). *PACS2* encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Clinical features in affected individuals include neonatal/early-infantile-onset epilepsy, hypotonia, global developmental delay, intellectual disability, autism or autistic behavior, cerebellar dysgenesis, and facial dysmorphism. Other less common features include distal limb abnormalities, ocular abnormalities, and cardiac defects. Two missense variants that have been reported in 14 probands in 5 publications (PMIDs: 29656858, 30684285, 34894068, 35770754, 36645641) are included in this curation. Of note, 13 of 14 probands had the recurrent PACS2 p.Glu209Lys variant. Most variants are *de novo*. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The recurrent p.Glu209Lys variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between PACS2 and client proteins, which may be consistent with a dominant-negative effect (PMID: 29656858). This gene-disease relationship is also supported by experimental evidence, including biochemical function and protein interaction studies. The paralog *PACS1* is involved in a neurodevelopmental disorder with overlapping features (Schuurs-Hoeijmakers syndrome), and PACS1 and PACS2 proteins interact with WDR37 (PMID: 34642815), which is also implicated in a neurodevelopmental disorder. In summary, there is definitive evidence supporting the relationship between *PACS2* and autosomal dominant developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 1, 2024 (SOP 10).
Inheritance Pattern: AD
Disease ID:MONDO:0054845
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Genitourinary; Hematologic; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PACS2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001100913.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 332 | 13 | 359 | ||
| missense | 5 | 376 | 143 | 40 | 564 | |
| nonsense | 5 | 1 | 6 | |||
| start loss | 0 | |||||
| frameshift | 1 | 7 | 1 | 9 | ||
| splice donor/acceptor (+/-2bp) | 12 | 2 | 14 | |||
| Total | 0 | 6 | 414 | 477 | 55 | 952 |
Highest pathogenic variant AF is 0.0000020641794
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001094383.2 | 25 | MANE Select | |
| Ensembl | ENSP00000393559.2 | 25 | MANE Select | |
| RefSeq | NP_001230056.1 | 23 | Standard | |
| RefSeq | NP_056012.2 | 24 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pacs2 | Danio rerio | Structure: whole organism Quality: semi-lethal (sensu genetics) abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- autophagosome assembly
- apoptotic process
- viral process
- protein localization to phagophore assembly site
- protein localization to plasma membrane
Molecular Function
- protein binding
- ion channel binding
Cellular Component
- mitochondrion
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000458164
- Coding exons
- 25
- Length
- 97585
- Individuals with no LoFs
- 125337
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125353
- p
- 0.0000638
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.24 | 414 | 563 | 0.735 | 0.0000371 | 5881 |
| Missense (PolyPhen) | 175 | 274.74 | 0.63698 | 2848 | ||
| Synonymous | -1.41 | 298 | 269 | 1.11 | 0.0000217 | 1765 |
| Loss of Function | 5.41 | 7 | 47.1 | 0.149 | 0.00000219 | 540 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00032 | 0.00019 | rare |
| Latino/Admixed American | 0.000031 | 0.000029 | rare |
| Ashkenazi Jewish | 0.00043 | 0.00040 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00010 | 0.000092 | rare |
| European (Non-Finnish) | 0.000036 | 0.000035 | rare |
| South Asian | 0.000036 | 0.000033 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments. {ECO:0000269|PubMed:15692563, ECO:0000269|PubMed:15692567}.;
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- LoFtool
- 0.444
- RVIS EVS
- -0.73
- RVIS percentile EVS
- 14.24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.253
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |