FURIN

Chr 15

furin, paired basic amino acid cleaving enzyme

Also known as: FUR, PACE, PCSK3, SPC1

NCBI Gene: 5045 ENSG00000140564 UniProt: P09958

The FURIN protein is an endoprotease that cleaves protein precursors at specific basic amino acid sequences within the secretory pathway, processing substrates including growth factors, hormones, and other signaling molecules. Pathogenic variants cause autosomal dominant developmental delay with variable intellectual disability, behavioral abnormalities, and distinctive facial features. This gene is highly constrained against loss-of-function variants, reflecting its essential role in cellular protein processing.

GeneReviews ResearchSummary from RefSeq, UniProt

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event takes place and the catalytic activity is acquired. Like other members of this convertase family, the product of this gene specifically cleaves substrates at single or paired basic residues. Some of its substrates include proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. It is thought to be one of the proteases responsible for the activation of HIV envelope glycoproteins gp160 and gp140, and may play a role in tumor progression. Unlike SARS-CoV and other coronaviruses, the spike protein of SARS-CoV-2 is thought to be uniquely cleaved by this protease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

GeneReviews ResearchGenerating clinical summary…

Clinical highlights

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.Based on population constraint only.

Active trials

296

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

—

Mechanism

📖

GeneReview available — FURIN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.47

OE 0.07 (0.03–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.50Z-score

OE missense 0.69 (0.64–0.76)

366 obs / 527.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.19)

0≤0.351.4

Missense OE?0.69 (0.64–0.76)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 3 / 40.7Missense obs/exp: 366 / 527.8Syn Z: -0.66

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

931 rare PASS variants

Rare truncating (LoF)

1 in 12,000

44 rare PASS variants

Rare synonymous (reference)

1 in 67

533 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FURIN. 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 71	1 in 10,000
South Asian	~43k	1 in 47	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 61	≈ 1 in 30,000
European (Finnish)	~27k	1 in 160	1 in 4,300
Admixed American	~22k	1 in 59	≈ 1 in 11,000
African / African American	~21k	1 in 64	none seen
East Asian	~20k	1 in 46	none seen
Ashkenazi Jewish	~13k	1 in 210	none seen
Middle Eastern	~2,884	1 in 71	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): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓