Is ACOX2 p.Ala487fs (c.1456_1457dup) pathogenic?

ACOX2 p.Ala487fs (c.14561457dup) is classified Uncertain significance in ACOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). Ultra-rare (popmax 0.0516%, sas); Associated with ACOX2-related disorder.

What condition is associated with ACOX2 p.Ala487fs (c.1456_1457dup)?

ACOX2 p.Ala487fs (c.1456_1457dup) is associated with ACOX2-related disorder (ClinVar).

How common is ACOX2 p.Ala487fs (c.1456_1457dup) in the general population?

ACOX2 p.Ala487fs (c.1456_1457dup) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

ACOX2 p.Ala487fs

c.1456_1457dup · rs769646916 · VCV2636916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Conditions

ACOX2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.77	GERP -1.8, phastCons 0.019
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% South Asian · 47/91,074 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00291% 47/1,614,034 alleles · ultra-rare

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: ACOX2
Protein: p.Ala487fs
Coding: c.1456_1457dup
MANE Select: NM_003500
dbSNP: rs769646916
Type: Duplication
Location: chr3:58524494 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49
Residue 487: a UniProt-annotated variant site (in cbas6; patient liver samples show absence of the protein; complete loss of fatty acid beta-oxidation activity)

Full ACOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACOX2-related disorder

Similar variants

ACOX2 p.Ala487Asp Uncertain significance ★ ⚠ same residue
ACOX2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
ACOX2 p.Gln146Ter Uncertain significance ★ same condition
ACOX2 p.Ala395Val Uncertain significance ⚠ same condition
ACOX2 p.Lys512Asn Uncertain significance ⚠ same condition
ACOX2 p.Thr465Met Uncertain significance ⚠ same condition
ACOX2 p.Val8Glu Uncertain significance ⚠ same condition
ACOX2 c.1156-3C>T Likely benign 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/acox2-p-ala487fs (accessed [today's date]).

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