# NM_003500.4(ACOX2):c.1456_1457dup (p.Ala487fs)

https://sugi.bio/variant/acox2-p-ala487fs

## Summary

**ACOX2 p.Ala487fs (c.1456_1457dup)** 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.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs769646916 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0516%, sas)

## For patients & families {#patients}

This is a change in the ACOX2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to ACOX2-related disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACOX2](https://sugi.bio/atlas/gene/ACOX2/) |
| Protein change (HGVS p.) | p.Ala487fs |
| Coding change (HGVS c.) | c.1456_1457dup |
| MANE Select transcript | [NM_003500](https://www.ncbi.nlm.nih.gov/nuccore/NM_003500) |
| dbSNP | [rs769646916](https://www.ncbi.nlm.nih.gov/snp/rs769646916/) |
| Variant type | Duplication |
| Location | chr3:58524494-58524495 (GRCh38) |
| ClinVar | [VCV2636916](https://www.ncbi.nlm.nih.gov/clinvar/variation/2636916/) |

**All HGVS expressions:** `NC_000003.11:g.58510222_58510223dup`, `NC_000003.12:g.58524495_58524496dup`, `NG_052668.1:g.17707_17708dup`, `NM_003500.4:c.1456_1457dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.767, GERP -1.75, phastCons 0.019 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.914, pLI 3.611e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 15**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0516%** (sas) · FAF95 0.0399% · FAF99 0.0357% · 47/91,074 in the highest group · 47/1,614,034 alleles overall — ultra-rare (popmax 0.0516%, sas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ACOX2** population constraint: LOEUF 0.914, pLI 3.611e-16, missense-Z 1.0739. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital bile acid synthesis defect 6** — Definitive (AR)

## Protein context {#protein}

Residue **487** lies in a UniProt-annotated variant site (in cbas6; patient liver samples show absence of the protein; complete loss of fatty acid beta-oxidation activity).

AlphaFold model confidence (whole protein): pLDDT 94.49, 91% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ACOX2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ACOX2's established molecular role includes 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA 24-hydroxylase activity.


### Pathways affected {#pathways}

ACOX2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta-oxidation of pristanoyl-CoA](https://reactome.org/content/detail/R-HSA-389887) | curated |
| [Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol](https://reactome.org/content/detail/R-HSA-193368) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA 24-hydroxylase activity.

**Biological process:** bile acid biosynthetic process, fatty acid beta-oxidation using acyl-CoA oxidase.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-12 |

## Associated conditions {#conditions}

[ACOX2-related disorder](https://sugi.bio/atlas/disease/acox2-related-disorder/).

**Reported phenotype names (ClinVar):** ACOX2-related disorder, ACOX2-related condition.

## Similar variants {#similar}

Related ACOX2 variant pages (same residue, condition, or type): [ACOX2 p.Ala487Asp](/variant/acox2-p-ala487asp), [ACOX2 p.Arg329Gln](/variant/acox2-p-arg329gln), [ACOX2 p.Gln146Ter](/variant/acox2-p-gln146ter), [ACOX2 p.Ala395Val](/variant/acox2-p-ala395val), [ACOX2 p.Lys512Asn](/variant/acox2-p-lys512asn), [ACOX2 p.Thr465Met](/variant/acox2-p-thr465met), [ACOX2 p.Val8Glu](/variant/acox2-p-val8glu), [ACOX2 c.1156-3C>T](/variant/acox2-c-1156-minus-3c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2636916). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*