Is PCSK9 p.Val280= (c.840G>A) pathogenic?

PCSK9 p.Val280= (c.840G>A) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). Very rare (popmax 0.00051%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with PCSK9 p.Val280= (c.840G>A)?

PCSK9 p.Val280= (c.840G>A) is associated with Cardiovascular phenotype, hypercholesterolemia, autosomal dominant, 3 (ClinVar).

How common is PCSK9 p.Val280= (c.840G>A) in the general population?

PCSK9 p.Val280= (c.840G>A) is very rare (popmax 0.00051%, nfe) (gnomAD).

PCSK9 p.Val280=

c.840G>A · rs1349838585 · VCV1763287

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -1.8
Overall
CADD	0.294	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00051% European (non-Finnish) · 6/1,177,482 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000373% 6/1,609,956 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PCSK9
Protein: p.Val280=
Coding: c.840G>A
MANE Select: NM_174936
dbSNP: rs1349838585
Type: single nucleotide variant
Location: chr1:55056033 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 280: the peptidase s8 domain

Full PCSK9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, autosomal dominant, 3

Similar variants

PCSK9 p.Val280Ala Uncertain significance ★★ ⚠ same residue
PCSK9 p.Arg215His Pathogenic/Likely pathogenic ★★ ⚠ same condition
PCSK9 p.Asp374His Pathogenic/Likely pathogenic ★★ ⚠ same condition
PCSK9 p.Asp374Tyr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PCSK9 c.1863+1G>A Uncertain significance ★★ same condition
PCSK9 c.1864-12G>A Uncertain significance ★★ same condition
PCSK9 c.207+5G>A Uncertain significance ★★ same condition
PCSK9 c.207+6G>C Uncertain significance ★★ same condition

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/pcsk9-p-val280 (accessed [today's date]).

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