Is PCSK9 p.Phe318= (c.954C>T) pathogenic?

PCSK9 p.Phe318= (c.954C>T) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-08). Very rare (popmax 0.00272%, afr); Associated with hypercholesterolemia, autosomal dominant, 3.

What condition is associated with PCSK9 p.Phe318= (c.954C>T)?

PCSK9 p.Phe318= (c.954C>T) is associated with hypercholesterolemia, autosomal dominant, 3, familial hypercholesterolemia (ClinVar).

How common is PCSK9 p.Phe318= (c.954C>T) in the general population?

PCSK9 p.Phe318= (c.954C>T) is very rare (popmax 0.00272%, afr) (gnomAD).

PCSK9 p.Phe318=

c.954C>T · rs1282082948 · VCV1767340

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00272%, 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 3.9	GERP -0.076, phastCons 1
Overall
CADD	13.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% African / African-American · 2/73,526 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000129% 2/1,544,994 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.Phe318=
Coding: c.954C>T
MANE Select: NM_174936
dbSNP: rs1282082948
Type: single nucleotide variant
Location: chr1:55056147 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 318: a β-strand; the peptidase s8 domain

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.Phe318Tyr Uncertain significance ★★ ⚠ same residue
PCSK9 p.Phe318fs Likely benign ★ 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-phe318 (accessed [today's date]).

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