PACS1

Chr 11AD

phosphofurin acidic cluster sorting protein 1

Also known as: MRD17, SHMS

NCBI Gene: 55690 ENSG00000175115 UniProt: Q6VY07 OMIM: 607492

The protein localizes trans-Golgi network membrane proteins by binding to phosphorylated cytosolic domains of target proteins like furin. Mutations cause Schuurs-Hoeijmakers syndrome through an autosomal dominant inheritance pattern. The pathogenic mechanism involves loss of function, which is consistent with the protein's critical role in Golgi trafficking.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Schuurs-Hoeijmakers syndromeMIM #615009

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Schuurs-Hoeijmakers syndrome · AD · ClinGen 2020

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

GOF*

Mechanism· G2P

📖

GeneReview available — PACS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.08 (0.04–0.18)

0≤0.351.4

Missense OE?0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 4 / 49.4Missense obs/exp: 302 / 545.9Syn Z: 1.48

Background carrier burden — how many people carry a rare variant somewhere in PACS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

910 rare PASS variants

Rare truncating (LoF)

1 in 2,700

81 rare PASS variants

Rare synonymous (reference)

1 in 92

493 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PACS1. 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 97	1 in 4,200
South Asian	~43k	1 in 99	1 in 1,100
Remaining (unassigned)	~30k	1 in 78	1 in 1,600
European (Finnish)	~27k	1 in 260	≈ 1 in 5,400
Admixed American	~22k	1 in 91	1 in 1,200
African / African American	~21k	1 in 92	1 in 530
East Asian	~20k	1 in 72	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 68	≈ 1 in 1,400

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): 21 of 24 coding exons well covered in gnomAD exomes; exons 1, 11, 14 marginal. Genomes: all 24.? see exons ↓