Is PCSK9 p.Pro331Ser (c.991C>T) pathogenic?

PCSK9 p.Pro331Ser (c.991C>T) is classified Uncertain significance in PCSK9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-05). AlphaMissense: likely benign (0.1066); Very rare (popmax 0.00254%, eas); Associated with hypercholesterolemia, autosomal dominant, 3.

What condition is associated with PCSK9 p.Pro331Ser (c.991C>T)?

PCSK9 p.Pro331Ser (c.991C>T) is associated with hypercholesterolemia, autosomal dominant, 3, familial hypercholesterolemia (ClinVar).

How common is PCSK9 p.Pro331Ser (c.991C>T) in the general population?

PCSK9 p.Pro331Ser (c.991C>T) is very rare (popmax 0.00254%, eas) (gnomAD).

What do computational predictors say about PCSK9 p.Pro331Ser (c.991C>T)?

AlphaMissense predicts likely benign (score 0.1066) — an in-silico prediction, not a clinical call.

PCSK9 p.Pro331Ser

c.991C>T · rs1644712856 · VCV3075394

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypercholesterolemia, autosomal dominant, 3

Computational evidence

Protein change
AlphaMissense	0.1066	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.96, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 24 kb · p 0.0038 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% East Asian · 1/39,344 alleles

Overall 0.000136% 2/1,467,848 alleles · very rare exomes 2/1,316,854 · genomes 0/150,994 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00254%	39,344
European (non-Finnish)	9.12e-05%	1,096,840

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.Pro331Ser
Coding: c.991C>T
MANE Select: NM_174936
dbSNP: rs1644712856
Type: single nucleotide variant
Location: chr1:55056184 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.03 · 66 PDB
Residue 331: 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.Pro331= Likely benign ★ 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-pro331ser (accessed [today's date]).

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