Is PCSK9 p.Pro604Ser (c.1810C>T) pathogenic?

PCSK9 p.Pro604Ser (c.1810C>T) is classified Uncertain significance in PCSK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00113%, sas); Associated with hypercholesterolemia, autosomal dominant, 3.

What condition is associated with PCSK9 p.Pro604Ser (c.1810C>T)?

PCSK9 p.Pro604Ser (c.1810C>T) is associated with hypercholesterolemia, autosomal dominant, 3 (ClinVar).

How common is PCSK9 p.Pro604Ser (c.1810C>T) in the general population?

PCSK9 p.Pro604Ser (c.1810C>T) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about PCSK9 p.Pro604Ser (c.1810C>T)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

PCSK9 p.Pro604Ser

c.1810C>T · rs2523278537 · VCV3072653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypercholesterolemia, autosomal dominant, 3

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -4.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	GERP 0.16, phastCons 0.002
Regional constraint	o/e 0.91	unconstrained · MANE · 24 kb · p 0.0038 · regional, not allelic
Overall
CADD	13.47	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 0.00113% South Asian · 1/88,776 alleles

Overall 0.000125% 2/1,605,312 alleles · very rare exomes 2/1,452,970 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00113%	88,776
European (non-Finnish)	8.5e-05%	1,176,436

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.Pro604Ser
Coding: c.1810C>T
MANE Select: NM_174936
dbSNP: rs2523278537
Type: single nucleotide variant
Location: chr1:55061503 (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

hypercholesterolemia, autosomal dominant, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PCSK9 p.Pro604= 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-pro604ser (accessed [today's date]).

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