Is APOE p.Arg185Ser (c.553C>A) pathogenic?

APOE p.Arg185Ser (c.553C>A) is classified Uncertain significance in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely benign (0.2402); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Arg185Ser (c.553C>A)?

APOE p.Arg185Ser (c.553C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is APOE p.Arg185Ser (c.553C>A) in the general population?

APOE p.Arg185Ser (c.553C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOE p.Arg185Ser (c.553C>A)?

AlphaMissense predicts likely benign (score 0.2402) — an in-silico prediction, not a clinical call.

APOE p.Arg185Ser

c.553C>A · VCV4127090

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2402 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,526,946)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2402	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.061	GERP -0.62
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	16.15	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

No allele count reported in gnomAD v4.1 (AN 1,526,946). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: APOE
Protein: p.Arg185Ser
Coding: c.553C>A
MANE Select: NM_000041
Type: single nucleotide variant
Location: chr19:44908849 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 185: the '8 x 22 aa approximate tandem repeats' region

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

Disease context

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

Similar variants

APOE p.Arg185= Likely benign ★ same residue
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Arg246Pro Uncertain significance ★★ same condition
APOE p.Arg56His Uncertain significance ★★ ⚠ same condition
APOE p.Gln119Pro Uncertain significance ★★ same condition
APOE p.Gln181His Uncertain significance ★★ ⚠ same condition
APOE p.Ser112Tyr Uncertain significance ★★ ⚠ same condition
APOE p.Trp294Cys 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-arg185ser (accessed [today's date]).

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