PACS2

Chr 14AD

phosphofurin acidic cluster sorting protein 2

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

NCBI Gene: 23241 ENSG00000179364 UniProt: Q86VP3 OMIM: 610423

PACS2 encodes a protein that maintains endoplasmic reticulum calcium homeostasis and tethers mitochondria to the endoplasmic reticulum. Loss-of-function mutations cause developmental and epileptic encephalopathy 66, inherited in an autosomal dominant pattern. The pathogenic mechanism involves disrupted cellular calcium regulation and impaired mitochondrial-ER communication.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.281 OMIM phenotype

Clinical Summary— PACS2

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · 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

2 unique Pathogenic / Likely Pathogenic· 435 VUS of 1314 total submissions

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Clinical Trials

1 active or recruiting trial — 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

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.15 (0.08–0.28)

0≤0.351.4

Missense OE?0.73 (0.68–0.80)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 7 / 47.1Missense obs/exp: 414 / 563.3Syn Z: -1.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPACS2-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.4587th %ile

GOF

0.3887th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.28

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

ClinVar Variant Classifications

1314 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS435

Likely Benign659

Benign138

Conflicting63

Likely Pathogenic

435

VUS

659

Likely Benign

138

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	0	2	0	0	2
VUS	18	374	30	13	435
Likely Benign	2	87	251	319	659
Benign	0	46	72	20	138
Conflicting	—				63
Total	20	509	353	352	1,297

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 87) ClinVar copy-number / structural variants overlap PACS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →