Is PCSK9 p.Pro174= (c.522C>G) pathogenic?

PCSK9 p.Pro174= (c.522C>G) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-19). Ultra-rare (popmax 0.0133%, amr); Associated with familial hypercholesterolemia.

What condition is associated with PCSK9 p.Pro174= (c.522C>G)?

PCSK9 p.Pro174= (c.522C>G) is associated with familial hypercholesterolemia (ClinVar).

How common is PCSK9 p.Pro174= (c.522C>G) in the general population?

PCSK9 p.Pro174= (c.522C>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

PCSK9 p.Pro174=

c.522C>G · rs373018373 · VCV2568394

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

familial hypercholesterolemia

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 -1.9	GERP -2.3
Overall
CADD	1.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,992 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00248% 40/1,613,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Finnishnot grpmax-eligible	0.00783%	12,774
European (non-Finnish)	0.00212%	47,199
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,878

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.Pro174=
Coding: c.522C>G
MANE Select: NM_174936
dbSNP: rs373018373
Type: single nucleotide variant
Location: chr1:55046645 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 174: the peptidase s8 domain; a UniProt-annotated variant site (found in patients with familial hypercholesterolemia carrying a homozygous ldlr mutation; acts as a disease modifier resulting in a mild phenotype)

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

Disease context

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

Similar variants

PCSK9 p.Pro174Leu Uncertain significance ★ ⚠ same residue
PCSK9 p.Pro174Ser 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-pro174 (accessed [today's date]).

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