# NM_003500.4(ACOX2):c.1186A>G (p.Met396Val)

https://sugi.bio/variant/acox2-p-met396val

## Summary

**ACOX2 p.Met396Val (c.1186A>G)** is classified **Likely benign** in ACOX2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0927); Rare (popmax 0.328%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs200815295 · 2 submitters · AlphaMissense likely benign · rare (popmax 0.328%, amr)

## For patients & families {#patients}

This is a change in the ACOX2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Met396Val |
| Coding change (HGVS c.) | c.1186A>G |
| MANE Select transcript | [NM_003500](https://www.ncbi.nlm.nih.gov/nuccore/NM_003500) |
| dbSNP | [rs200815295](https://www.ncbi.nlm.nih.gov/snp/rs200815295/) |
| Variant type | single nucleotide variant |
| Location | chr3:58526626-58526626 (GRCh38) |
| ClinVar | [VCV736750](https://www.ncbi.nlm.nih.gov/clinvar/variation/736750/) |

**All HGVS expressions:** `NC_000003.11:g.58512353T>C`, `NC_000003.12:g.58526626T>C`, `NG_052668.1:g.15577A>G`, `NM_003500.4:c.1186A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0927)
- REVEL 0.078 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.421 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.7, GERP -4.66, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 10.22**. 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 0.95** across the covering region of the MANE Select transcript (58,505,227–58,535,106), spanning 29,879 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.20 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.328%** (amr) · FAF95 0.291% · FAF99 0.276% · 197/60,024 in the highest group · 201/1,614,174 alleles overall — rare (popmax 0.328%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.328% | 305 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,502 |
| African / African-American | 0.00133% | 75,054 |
| European (non-Finnish) | 0.000169% | 590,019 |

*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 **396** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-26.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-12-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |

**Reported phenotype names (ClinVar):** not provided, ACOX2-related disorder, ACOX2-related condition, none provided.

## Similar variants {#similar}

Related ACOX2 variant pages (same residue, condition, or type): [ACOX2 p.Ala106Val](/variant/acox2-p-ala106val), [ACOX2 p.Ala48Glu](/variant/acox2-p-ala48glu), [ACOX2 p.Arg197Gln](/variant/acox2-p-arg197gln), [ACOX2 p.Arg197Trp](/variant/acox2-p-arg197trp), [ACOX2 p.Arg215Trp](/variant/acox2-p-arg215trp), [ACOX2 p.Arg318His](/variant/acox2-p-arg318his), [ACOX2 p.Arg323Cys](/variant/acox2-p-arg323cys), [ACOX2 p.Arg323His](/variant/acox2-p-arg323his).

### 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 736750). 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.*