Is PCSK9 p.Phe205= (c.615C>T) pathogenic?

PCSK9 p.Phe205= (c.615C>T) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-08-30). Very rare (popmax 0.0022%, sas); Associated with Cardiovascular phenotype.

What condition is associated with PCSK9 p.Phe205= (c.615C>T)?

PCSK9 p.Phe205= (c.615C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, autosomal dominant, 3 (ClinVar).

How common is PCSK9 p.Phe205= (c.615C>T) in the general population?

PCSK9 p.Phe205= (c.615C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

PCSK9 p.Phe205=

c.615C>T · rs759797943 · VCV922592

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, 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 -3.1	GERP -2.1
Overall
CADD	5.905	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000821% 12/1,461,734 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,537
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000763%	131,112

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.Phe205=
Coding: c.615C>T
MANE Select: NM_174936
dbSNP: rs759797943
Type: single nucleotide variant
Location: chr1:55052369 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 205: the peptidase s8 domain; a β-strand

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.Phe205fs 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
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-phe205 (accessed [today's date]).

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