Is APOA4 p.Arg134Pro (c.401G>C) pathogenic?

APOA4 p.Arg134Pro (c.401G>C) is classified Uncertain significance in APOA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.6905); Absent from gnomAD v4.1.

How common is APOA4 p.Arg134Pro (c.401G>C) in the general population?

APOA4 p.Arg134Pro (c.401G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOA4 p.Arg134Pro (c.401G>C)?

AlphaMissense predicts likely pathogenic (score 0.6905) — an in-silico prediction, not a clinical call.

APOA4 p.Arg134Pro

c.401G>C · VCV4641689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6905 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6905	likely pathogenic · top 7% in APOA4
REVEL	0.515	indeterminate
SaProt	LLR -14.93	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 -1.2	GERP 2.4
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	20.2	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: APOA4
Protein: p.Arg134Pro
Coding: c.401G>C
MANE Select: NM_000482
Type: single nucleotide variant
Location: chr11:116821657 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 134: the '13 x 22 aa approximate tandem repeats' region; an α-helix

Full APOA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOA4 p.Arg134His Benign/Likely benign ★★ ⚠ same residue
APOA4 p.Arg134Cys Uncertain significance ★ ⚠ same residue
APOA4 p.Arg134Ser Uncertain significance ★ ⚠ same residue
APOA4 p.Ala172Thr Uncertain significance ★★ ⚠ same type
APOA4 p.Ala333Val Uncertain significance ★★ ⚠ same type
APOA4 p.Ala60Asp Uncertain significance ★★ ⚠ same type
APOA4 p.Arg166Ser Uncertain significance ★★ ⚠ same type
APOA4 p.Arg275Cys Uncertain significance ★★ ⚠ same type

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/apoa4-p-arg134pro (accessed [today's date]).

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