Is PCSK9 p.Pro604= (c.1812A>C) pathogenic?

PCSK9 p.Pro604= (c.1812A>C) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-01). Ultra-rare (popmax 0.0329%, mid); Associated with familial hypercholesterolemia.

What condition is associated with PCSK9 p.Pro604= (c.1812A>C)?

PCSK9 p.Pro604= (c.1812A>C) is associated with familial hypercholesterolemia, hypercholesterolemia, autosomal dominant, 3 (ClinVar).

How common is PCSK9 p.Pro604= (c.1812A>C) in the general population?

PCSK9 p.Pro604= (c.1812A>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

PCSK9 p.Pro604=

c.1812A>C · rs777190873 · VCV1570575

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

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 -3.3	GERP -2.4
Overall
CADD	1.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,072 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000685% 11/1,605,296 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,036
South Asian	0.00676%	14,799
European (non-Finnish)	0.000255%	392,157

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.Pro604=
Coding: c.1812A>C
MANE Select: NM_174936
dbSNP: rs777190873
Type: single nucleotide variant
Location: chr1:55061505 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 604: the 'c-terminal domain' region

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

Also linked: hypercholesterolemia, autosomal dominant, 3

Similar variants

PCSK9 p.Pro604Ser Uncertain significance ★ ⚠ 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-pro604 (accessed [today's date]).

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