Is PCSK9 p.Leu289= (c.867G>A) pathogenic?

PCSK9 p.Leu289= (c.867G>A) is classified Likely benign in PCSK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-30). Very rare (popmax 0.00111%, sas); Associated with Cardiovascular phenotype.

What condition is associated with PCSK9 p.Leu289= (c.867G>A)?

PCSK9 p.Leu289= (c.867G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is PCSK9 p.Leu289= (c.867G>A) in the general population?

PCSK9 p.Leu289= (c.867G>A) is very rare (popmax 0.00111%, sas) (gnomAD).

PCSK9 p.Leu289=

c.867G>A · VCV4861684

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

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 1.2	GERP -1.3, phastCons 0.99
Overall
CADD	7.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,402 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,607,144 alleles · very rare exomes 4/1,454,882 · genomes 0/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,402
European (non-Finnish)	0.000255%	391,995

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.Leu289=
Coding: c.867G>A
MANE Select: NM_174936
Type: single nucleotide variant
Location: chr1:55056060 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 289: a β-strand; 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

Similar variants

PCSK9 p.Asp374His Pathogenic/Likely pathogenic ★★ ⚠ same condition
PCSK9 c.207+5G>A Uncertain significance ★★ same condition
PCSK9 p.Ala100Gly Uncertain significance ★★ ⚠ same condition
PCSK9 p.Ala220Thr Uncertain significance ★★ ⚠ same condition
PCSK9 p.Ala242Val Uncertain significance ★★ ⚠ same condition
PCSK9 p.Ala26Thr Uncertain significance ★★ ⚠ same condition
PCSK9 p.Ala26Val Uncertain significance ★★ ⚠ same condition
PCSK9 p.Ala299Thr 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-leu289 (accessed [today's date]).

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