Is APOA4 p.Arg134Ser (c.400C>A) pathogenic?

APOA4 p.Arg134Ser (c.400C>A) is classified Uncertain significance in APOA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.2198); Absent from gnomAD v4.1.

How common is APOA4 p.Arg134Ser (c.400C>A) in the general population?

APOA4 p.Arg134Ser (c.400C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOA4 p.Arg134Ser (c.400C>A)?

AlphaMissense predicts likely benign (score 0.2198) — an in-silico prediction, not a clinical call.

APOA4 p.Arg134Ser

c.400C>A · rs774077750 · VCV2276126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2198 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2198	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -8.83	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 1.3	GERP 1.3, phastCons 0.61
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	17.1	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

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.Arg134Ser
Coding: c.400C>A
MANE Select: NM_000482
dbSNP: rs774077750
Type: single nucleotide variant
Location: chr11:116821658 (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.Arg134Pro 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-arg134ser (accessed [today's date]).

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