Is PCSK9 p.Ala239= (c.717C>T) pathogenic?

PCSK9 p.Ala239= (c.717C>T) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-16). Ultra-rare (popmax 0.016%, afr); Associated with Cardiovascular phenotype.

What condition is associated with PCSK9 p.Ala239= (c.717C>T)?

PCSK9 p.Ala239= (c.717C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, autosomal dominant, 3 (ClinVar).

How common is PCSK9 p.Ala239= (c.717C>T) in the general population?

PCSK9 p.Ala239= (c.717C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

PCSK9 p.Ala239=

c.717C>T · rs370145766 · VCV1455601

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

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 -4.8	GERP -1.4
Overall
CADD	5.283	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/75,062 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.0031% 50/1,613,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,255
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Admixed American	0.00333%	30,005
European (non-Finnish)	0.00263%	38,064
Finnishnot grpmax-eligible	0.00158%	63,106
South Asian	0.0011%	91,074

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.Ala239=
Coding: c.717C>T
MANE Select: NM_174936
dbSNP: rs370145766
Type: single nucleotide variant
Location: chr1:55052709 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 239: a disulfide bond; the peptidase s8 domain; a UniProt-annotated variant site (sequence variant); a turn

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: familial hypercholesterolemia hypercholesterolemia, autosomal dominant, 3

Similar variants

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
PCSK9 c.208-6G>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-ala239 (accessed [today's date]).

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