# NM_004035.7(ACOX1):c.737G>A (p.Arg246His)

https://sugi.bio/variant/acox1-p-arg246his

## Summary

**ACOX1 p.Arg246His (c.737G>A)** is classified **Uncertain significance** in ACOX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-15). AlphaMissense: likely benign (0.1565); Very rare (popmax 0.00195%, nfe); Associated with peroxisomal acyl-CoA oxidase deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1392899105 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00195%, nfe)

## For patients & families {#patients}

This is a change in the ACOX1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to peroxisomal acyl-CoA oxidase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACOX1 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Peroxisomal acyl-CoA oxidase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Abnormality of visual evoked potentials — Very frequent (99-80%)
- Hypodontia — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004543/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACOX1](https://sugi.bio/atlas/gene/ACOX1/) |
| Protein change (HGVS p.) | p.Arg246His |
| Coding change (HGVS c.) | c.737G>A |
| MANE Select transcript | [NM_004035](https://www.ncbi.nlm.nih.gov/nuccore/NM_004035) |
| dbSNP | [rs1392899105](https://www.ncbi.nlm.nih.gov/snp/rs1392899105/) |
| Variant type | single nucleotide variant |
| Location | chr17:75955603-75955603 (GRCh38) |
| ClinVar | [VCV888589](https://www.ncbi.nlm.nih.gov/clinvar/variation/888589/) |

**All HGVS expressions:** `NC_000017.10:g.73951684C>T`, `NC_000017.11:g.75955603C>T`, `NG_008190.1:g.28761G>A`, `NM_001185039.2:c.623G>A`, `NM_004035.7:c.737G>A`, `NM_007292.6:c.737G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1565)
- REVEL 0.652 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.848 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 5.965, GERP 1.85, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.9**. 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.*
- Regional missense constraint: **o/e 0.68** across the covering region of the MANE Select transcript (75,949,875–75,979,073), spanning 29,198 bp. Chi-square p 1.3e-14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00195%** (nfe) · FAF95 0.0013% · FAF99 0.00108% · 23/1,180,026 in the highest group · 24/1,613,994 alleles overall — very rare (popmax 0.00195%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00195% | 51,305 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,008 |

*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}

**ACOX1** population constraint: LOEUF 0.67, pLI 1.7103e-05, missense-Z 3.067; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **Mitchell syndrome** — Definitive (AD)
- **peroxisomal acyl-CoA oxidase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.95, 87% of residues very-high.

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

*Describes the biological roles of ACOX1 (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:** ACOX1's established molecular role includes acyl-CoA oxidase activity.


### Pathways affected {#pathways}

ACOX1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta-oxidation of very long chain fatty acids](https://reactome.org/content/detail/R-HSA-390247) | other |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | other |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |
| [TYSND1 cleaves peroxisomal proteins](https://reactome.org/content/detail/R-HSA-9033500) | electronic |
| [alpha-linolenic acid (ALA) metabolism](https://reactome.org/content/detail/R-HSA-2046106) | other |

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

**Molecular function:** acyl-CoA oxidase activity, PDZ domain binding, protein homodimerization activity, FAD binding, long-chain fatty acyl-CoA oxidase activity.

**Biological process:** very long-chain fatty acid metabolic process, generation of precursor metabolites and energy, lipid metabolic process, prostaglandin metabolic process, fatty acid catabolic process, peroxisome fission.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-15.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-15 |

## Associated conditions {#conditions}

[peroxisomal acyl-CoA oxidase deficiency](https://sugi.bio/atlas/disease/peroxisomal-acyl-coa-oxidase-deficiency/).

**Reported phenotype names (ClinVar):** Acyl-CoA oxidase deficiency, Inborn genetic diseases, STRAIGHT-CHAIN ACYL-CoA OXIDASE DEFICIENCY, Pseudoneonatal adrenoleukodystrophy, Peroxisomal acyl-CoA oxidase deficiency.

## Similar variants {#similar}

Related ACOX1 variant pages (same residue, condition, or type): [ACOX1 p.Arg246Cys](/variant/acox1-p-arg246cys), [ACOX1 c.538+1G>A](/variant/acox1-c-538-plus-1g-a), [ACOX1 c.945-1G>C](/variant/acox1-c-945-minus-1g-c), [ACOX1 p.Arg148Ter](/variant/acox1-p-arg148ter), [ACOX1 p.Arg302Ter](/variant/acox1-p-arg302ter), [ACOX1 p.Arg94Ter](/variant/acox1-p-arg94ter), [ACOX1 p.Asn237Ser](/variant/acox1-p-asn237ser), [ACOX1 p.Gln114Ter](/variant/acox1-p-gln114ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 888589). 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.*