Is PCSK9 p.Pro446= (c.1338C>T) pathogenic?

PCSK9 p.Pro446= (c.1338C>T) is classified Uncertain significance in PCSK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 8.48e-05%, nfe); Associated with hypobetalipoproteinemia.

What condition is associated with PCSK9 p.Pro446= (c.1338C>T)?

PCSK9 p.Pro446= (c.1338C>T) is associated with hypobetalipoproteinemia, hypercholesterolemia, autosomal dominant, 3 (ClinVar).

How common is PCSK9 p.Pro446= (c.1338C>T) in the general population?

PCSK9 p.Pro446= (c.1338C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

PCSK9 p.Pro446=

c.1338C>T · rs1644730812 · VCV876490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hypobetalipoproteinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.37	GERP 0.013
Overall
CADD	7.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,862 alleles

Overall 6.2e-05% 1/1,613,094 alleles · very rare exomes 1/1,460,740 · genomes 0/152,354 · joint denominator

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.Pro446=
Coding: c.1338C>T
MANE Select: NM_174936
dbSNP: rs1644730812
Type: single nucleotide variant
Location: chr1:55058193 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 446: an α-helix; the peptidase s8 domain

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

Disease context

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

Also linked: hypercholesterolemia, autosomal dominant, 3

Similar variants

PCSK9 p.Pro446Leu 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-pro446 (accessed [today's date]).

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