Is APOA5 p.Ile296Arg (c.887T>G) pathogenic?

APOA5 p.Ile296Arg (c.887T>G) is classified Uncertain significance in APOA5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-30). AlphaMissense: likely pathogenic (0.9058); Ultra-rare (popmax 0.0167%, amr).

How common is APOA5 p.Ile296Arg (c.887T>G) in the general population?

APOA5 p.Ile296Arg (c.887T>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about APOA5 p.Ile296Arg (c.887T>G)?

AlphaMissense predicts likely pathogenic (score 0.9058) — an in-silico prediction, not a clinical call.

APOA5 p.Ile296Arg

c.887T>G · rs761343549 · VCV1196373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9058	likely pathogenic · top 1% in APOA5
REVEL	0.663	pathogenic-leaning
SaProt	LLR -15.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,729 bp · p 0.086 · 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

Grpmax group 0.0167% Admixed American · 10/60,016 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000743% 12/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,180,052

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: APOA5
Protein: p.Ile296Arg
Coding: c.887T>G
MANE Select: NM_001371904
dbSNP: rs761343549
Type: single nucleotide variant
Location: chr11:116790342 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.38

Full APOA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOA5 p.Ile296fs Conflicting classifications of pathogenicity ★ same residue
APOA5 p.Gln97Ter Pathogenic ★★ same type
APOA5 c.161+3G>A Uncertain significance ★★ same type
APOA5 c.161+5G>C Uncertain significance ★★ same type
APOA5 p.Ala105Ser Uncertain significance ★★ ⚠ same type
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same type
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same type
APOA5 p.Ala82Val 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/apoa5-p-ile296arg (accessed [today's date]).

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