PACS2

Chr 14AD

phosphofurin acidic cluster sorting protein 2

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

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

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 66MIM #618067

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · genetic developmental and epileptic encephalopathy · AD · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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

Background carrier burden — how many people carry a rare variant somewhere in PACS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 64

1,068 rare PASS variants

Rare truncating (LoF)

1 in 3,100

96 rare PASS variants

Rare synonymous (reference)

1 in 52

626 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PACS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 6,200
South Asian	~43k	1 in 46	1 in 1,600
Remaining (unassigned)	~30k	1 in 54	1 in 580
European (Finnish)	~27k	1 in 140	1 in 1,900
Admixed American	~22k	1 in 54	1 in 3,200
African / African American	~21k	1 in 68	1 in 1,300
East Asian	~20k	1 in 60	1 in 1,500
Ashkenazi Jewish	~13k	1 in 200	1 in 2,100
Middle Eastern	~2,884	1 in 65	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 18 of 25 coding exons well covered in gnomAD exomes; exons 1, 3, 6, 14, 15 and 2 more marginal. Genomes: all 25.? see exons ↓