Is PCSK9 p.Pro345= (c.1035G>A) pathogenic?

PCSK9 p.Pro345= (c.1035G>A) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-07). Very rare (popmax 0.00381%, nfe); Associated with hypercholesterolemia, autosomal dominant, 3.

What condition is associated with PCSK9 p.Pro345= (c.1035G>A)?

PCSK9 p.Pro345= (c.1035G>A) is associated with hypercholesterolemia, autosomal dominant, 3, familial hypercholesterolemia (ClinVar).

How common is PCSK9 p.Pro345= (c.1035G>A) in the general population?

PCSK9 p.Pro345= (c.1035G>A) is very rare (popmax 0.00381%, nfe) (gnomAD).

PCSK9 p.Pro345=

c.1035G>A · rs767809932 · VCV1172041

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

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	GERP -2.4
Overall
CADD	2.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,028 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.0031% 50/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,223
East Asian	0.00223%	44,886
South Asian	0.0022%	45,546
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,934

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.Pro345=
Coding: c.1035G>A
MANE Select: NM_174936
dbSNP: rs767809932
Type: single nucleotide variant
Location: chr1:55057369 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 345: a β-strand; a disulfide bond; 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.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-pro345 (accessed [today's date]).

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