Is PCSK7 p.Pro559Arg (c.1676C>G) pathogenic?

PCSK7 p.Pro559Arg (c.1676C>G) is classified Uncertain significance in PCSK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0821); Absent from gnomAD v4.1.

How common is PCSK7 p.Pro559Arg (c.1676C>G) in the general population?

PCSK7 p.Pro559Arg (c.1676C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PCSK7 p.Pro559Arg (c.1676C>G)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

PCSK7 p.Pro559Arg

c.1676C>G · VCV4838080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0821	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 64 bp · p 0.033 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PCSK7
Protein: p.Pro559Arg
Coding: c.1676C>G
MANE Select: NM_004716
Type: single nucleotide variant
Location: chr11:117208912 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.92
Residue 559: the p/homo b domain

Full PCSK7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCSK7 p.Arg560Gly Uncertain significance ★★ ⚠ same type
PCSK7 p.Lys545Thr Uncertain significance ★★ ⚠ same type
PCSK7 c.1786+7C>T Benign ★★ same type
PCSK7 p.Leu590= Likely benign ★★ same type
PCSK7 p.Pro777Leu Benign ★★ same type
PCSK7 c.1691+1G>A Uncertain significance ★ same type
PCSK7 p.Ala26Thr Uncertain significance ★ ⚠ same type
PCSK7 p.Ala273Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pcsk7-p-pro559arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown