Is APOE p.Arg154Ser (c.460C>A) pathogenic?

APOE p.Arg154Ser (c.460C>A) is classified Pathogenic/Likely pathogenic in APOE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.615); Ultra-rare (popmax 0.0154%, amr); Associated with familial hypercholesterolemia.

What condition is associated with APOE p.Arg154Ser (c.460C>A)?

APOE p.Arg154Ser (c.460C>A) is associated with familial hypercholesterolemia, hyperlipoproteinemia type 3 (ClinVar).

How common is APOE p.Arg154Ser (c.460C>A) in the general population?

APOE p.Arg154Ser (c.460C>A) is ultra-rare (popmax 0.0154%, amr) (gnomAD).

What do computational predictors say about APOE p.Arg154Ser (c.460C>A)?

AlphaMissense predicts likely pathogenic (score 0.615) — an in-silico prediction, not a clinical call.

APOE p.Arg154Ser

c.460C>A · rs121918393 · VCV17850

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.615	likely pathogenic ✓ concordant with ClinVar
REVEL	0.67	pathogenic-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% Admixed American · 8/52,080 alleles

Filtering AF 0.00758% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00555%

Overall 0.00333% 52/1,559,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0154%	6,510
European (non-Finnish)	0.00364%	27,471
Remaining individualsnot grpmax-eligible	0.00331%	30,220

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: APOE
Protein: p.Arg154Ser
Coding: c.460C>A
MANE Select: NM_000041
dbSNP: rs121918393
Type: single nucleotide variant
Location: chr19:44908756 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 154: the '8 x 22 aa approximate tandem repeats' region; a UniProt-annotated variant site (in hlpp3; apoe2-type); a UniProt-annotated variant site (in hlpp3; apoe2 christchurch; decreased binding to ldl receptor); an α-helix

Full APOE 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

Also linked: hyperlipoproteinemia type 3

Similar variants

APOE p.Arg154His Likely pathogenic ★ ⚠ same residue
APOE p.Arg154Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
APOE p.Arg154Leu Likely pathogenic ★ same residue
APOE p.Arg154= Likely benign ★ same residue
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Trp228Ter Likely pathogenic ★★ same condition
APOE p.Arg269Gly Uncertain significance ★★ ⚠ same condition
APOE p.Gln181His 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/apoe-p-arg154ser (accessed [today's date]).

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