Is PCSK9 p.Arg46= (c.138T>G) pathogenic?

PCSK9 p.Arg46= (c.138T>G) is classified Likely benign in PCSK9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-09). Absent from gnomAD v4.1; Associated with familial hypercholesterolemia.

What condition is associated with PCSK9 p.Arg46= (c.138T>G)?

PCSK9 p.Arg46= (c.138T>G) is associated with familial hypercholesterolemia (ClinVar).

How common is PCSK9 p.Arg46= (c.138T>G) in the general population?

PCSK9 p.Arg46= (c.138T>G) is absent from gnomAD v4.1 (gnomAD).

PCSK9 p.Arg46=

c.138T>G · rs2523164783 · VCV1771530

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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	GERP -2
Overall
CADD	7.655	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PCSK9
Protein: p.Arg46=
Coding: c.138T>G
MANE Select: NM_174936
dbSNP: rs2523164783
Type: single nucleotide variant
Location: chr1:55039975 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 46: a UniProt-annotated variant site (correlated with lower plasma levels of low-density lipoprotein cholesterol; reduced phosphorylation at ser-47)

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.Arg46Cys Uncertain significance ★★ ⚠ same residue
PCSK9 p.Arg46Leu Benign/Likely benign ★★ same residue
PCSK9 p.Arg46Ser 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

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-arg46 (accessed [today's date]).

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