Is APOE p.Arg176Pro (c.527G>C) pathogenic?

APOE p.Arg176Pro (c.527G>C) is classified Uncertain significance in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely pathogenic (0.8375); Absent from gnomAD v4.1; Associated with lipoprotein glomerulopathy.

What condition is associated with APOE p.Arg176Pro (c.527G>C)?

APOE p.Arg176Pro (c.527G>C) is associated with lipoprotein glomerulopathy (ClinVar).

How common is APOE p.Arg176Pro (c.527G>C) in the general population?

APOE p.Arg176Pro (c.527G>C) is absent from gnomAD v4.1 (gnomAD).

How is Lipoprotein glomerulopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APOE p.Arg176Pro (c.527G>C)?

AlphaMissense predicts likely pathogenic (score 0.8375) — an in-silico prediction, not a clinical call.

APOE p.Arg176Pro

c.527G>C · VCV4293341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8375 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lipoprotein glomerulopathy

Computational evidence

Protein change
AlphaMissense	0.8375	likely pathogenic · top 3% in APOE
REVEL	0.604	indeterminate
SaProt	LLR -10.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APOE
Protein: p.Arg176Pro
Coding: c.527G>C
MANE Select: NM_000041
Type: single nucleotide variant
Location: chr19:44908823 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 176: the '8 x 22 aa approximate tandem repeats' region; a UniProt-annotated variant site (in hlpp3; apoe2, apoe2 fukuoka, apoe1 weisgraber and apoe3**; apoe3** is associated with hlpp3; changed protein structure; decreased binding to ldlr and other lipoprotein receptors; decreased in vitro binding to heparin; no effect on distribution among plasma lipoproteins); an α-helix

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

Disease context

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

For Lipoprotein glomerulopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Arg269Gly Uncertain significance ★★ ⚠ same condition
APOE p.Glu230Lys Uncertain significance ★★ ⚠ same condition
APOE p.Gly145Asp Uncertain significance ★★ same condition
APOE p.Ala217= Benign/Likely benign ★★ same condition
APOE p.Ala23= Likely benign ★★ same condition
APOE p.Asp83= Likely benign ★★ same condition
APOE p.Arg163His Conflicting classifications of pathogenicity ★ ⚠ 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-arg176pro (accessed [today's date]).

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