FURIN

Chr 15

furin, paired basic amino acid cleaving enzyme

Also known as: FUR, PACE, PCSK3, SPC1

NCBI Gene: 5045 ENSG00000140564 UniProt: P09958 OMIM: 136950

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 OMIM 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 OMIM ResearchGenerating clinical summary…

LOEUF 0.19

Clinical Summary— FURIN

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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

100 VUS of 127 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — FURIN

Authoritative clinical overview · Recommended first read

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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

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

VUS100

Likely Benign6

Benign1

100

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	100	0	0	100
Likely Benign	2	1	3	6
Benign	0	1	0	1
Total	102	2	3	107

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap FURIN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →