Is PCSK9 p.Ser89= (c.267G>A) pathogenic?

PCSK9 p.Ser89= (c.267G>A) is classified Benign/Likely benign in PCSK9 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-06). Ultra-rare (popmax 0.024%, afr); Associated with hypercholesterolemia, autosomal dominant, 3.

What condition is associated with PCSK9 p.Ser89= (c.267G>A)?

PCSK9 p.Ser89= (c.267G>A) is associated with hypercholesterolemia, autosomal dominant, 3, familial hypercholesterolemia (ClinVar).

How common is PCSK9 p.Ser89= (c.267G>A) in the general population?

PCSK9 p.Ser89= (c.267G>A) is ultra-rare (popmax 0.024%, afr) (gnomAD).

PCSK9 p.Ser89=

c.267G>A · rs373551845 · VCV627675

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

hypercholesterolemia, autosomal dominant, 3

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 -1.6	GERP -1.2
Overall
CADD	5.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/75,054 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00229% 37/1,614,184 alleles · ultra-rare exomes 26/1,461,850 · genomes 11/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,170
South Asian	0.00769%	13,012
Admixed American	0.00167%	60,032
European (non-Finnish)	0.000932%	107,276

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.Ser89=
Coding: c.267G>A
MANE Select: NM_174936
dbSNP: rs373551845
Type: single nucleotide variant
Location: chr1:55043902 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 89: the inhibitor i9 domain; an α-helix

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

Disease context

hypercholesterolemia, autosomal dominant, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

PCSK9 p.Ser89Trp Benign/Likely benign ★★ same residue
PCSK9 p.Ser89Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-ser89 (accessed [today's date]).

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