PCSK7

Chr 11

proprotein convertase subtilisin/kexin type 7

Also known as: LPC, PC7, PC8, SPC7

NCBI Gene: 9159 ENSG00000160613 UniProt: Q16549

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. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It can process proalbumin and is thought to be responsible for the activation of HIV envelope glycoproteins gp160 and gp140. This gene has been implicated in the transcriptional regulation of housekeeping genes and plays a role in the regulation of iron metabolism. A t(11;14)(q23;q32) chromosome translocation associated with B-cell lymphoma occurs between this gene and its inverted counterpart. [provided by RefSeq, Feb 2014]

Research

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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.004

Z-score 3.80

OE 0.31 (0.19–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.49Z-score

OE missense 0.81 (0.74–0.88)

373 obs / 463.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.19–0.51)

0≤0.351.4

Missense OE?0.81 (0.74–0.88)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 11 / 35.4Missense obs/exp: 373 / 463.0Syn Z: 0.38

Background carrier burden — how many people carry a rare variant somewhere in PCSK7?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 55

777 rare PASS variants

Rare truncating (LoF)

1 in 1,600

91 rare PASS variants

Rare synonymous (reference)

1 in 93

321 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PCSK7. 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 77	1 in 1,500
South Asian	~43k	1 in 54	1 in 580
Remaining (unassigned)	~30k	1 in 50	1 in 770
European (Finnish)	~27k	1 in 180	1 in 750
Admixed American	~22k	1 in 71	1 in 310
African / African American	~21k	1 in 64	1 in 1,300
East Asian	~20k	1 in 71	1 in 800
Ashkenazi Jewish	~13k	1 in 390	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 90	≈ 1 in 2,900

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): 8 of 15 coding exons well covered in gnomAD exomes; exons 14, 15, 16 poorly covered; exons 6, 9, 12, 17 marginal. Genomes: 10 of 15 (exons 13, 14, 15, 16, 17 below).? see exons ↓