# NM_002858.4(ABCD3):c.1472del (p.Pro491fs)

https://sugi.bio/variant/abcd3-p-pro491fs

## Summary

**ABCD3 p.Pro491fs (c.1472del)** is classified **Uncertain significance** in ABCD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the ABCD3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ABCD3](https://sugi.bio/atlas/gene/ABCD3/) |
| Protein change (HGVS p.) | p.Pro491fs |
| Coding change (HGVS c.) | c.1472del |
| MANE Select transcript | [NM_002858](https://www.ncbi.nlm.nih.gov/nuccore/NM_002858) |
| Variant type | Deletion |
| Location | chr1:94498789-94498789 (GRCh38) |
| ClinVar | [VCV3645578](https://www.ncbi.nlm.nih.gov/clinvar/variation/3645578/) |

**All HGVS expressions:** `NC_000001.10:g.94964346del`, `NC_000001.11:g.94498790del`, `NG_008865.1:g.85414del`, `NG_008865.2:g.118661del`, `NM_002858.4:c.1472del`

## 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 11.922, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.484, pLI 0.99014), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**ABCD3** population constraint: LOEUF 0.484, pLI 0.99014, missense-Z 2.4773. *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 5** — Limited (AR)

## Protein context {#protein}

Residue **491** lies in the abc transporter domain.

AlphaFold model confidence (whole protein): pLDDT 83.39, 52% of residues very-high.

**9 experimental structure(s)** (PDB): [8Z0F](https://www.rcsb.org/structure/8Z0F), [8Z9X](https://www.rcsb.org/structure/8Z9X), [9NGJ](https://www.rcsb.org/structure/9NGJ), [9NGM](https://www.rcsb.org/structure/9NGM), [9W62](https://www.rcsb.org/structure/9W62), [9W63](https://www.rcsb.org/structure/9W63).

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

*Describes the biological roles of ABCD3 (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:** ABCD3's established molecular role includes long-chain fatty acid transmembrane transporter activity. p.Pro491fs falls in the abc transporter domain.


### Pathways affected {#pathways}

ABCD3 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [Synthesis of bile acids and bile salts via 24-hydroxycholesterol](https://reactome.org/content/detail/R-HSA-193775) | curated |
| [Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol](https://reactome.org/content/detail/R-HSA-193368) | curated |

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

**Molecular function:** long-chain fatty acid transmembrane transporter activity, ATP binding, ATP hydrolysis activity, ATPase-coupled transmembrane transporter activity, protein homodimerization activity, fatty acyl-CoA hydrolase activity.

**Biological process:** very long-chain fatty acid metabolic process, fatty acid biosynthetic process, fatty acid beta-oxidation, peroxisome organization, long-chain fatty acid import into peroxisome, very long-chain fatty acid catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-12 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ABCD3 variant pages (same residue, condition, or type): [ABCD3 c.1387-19del](/variant/abcd3-c-1387-minus-19del), [ABCD3 c.1387-4del](/variant/abcd3-c-1387-minus-4del), [ABCD3 c.1530+12del](/variant/abcd3-c-1530-plus-12del), [ABCD3 c.1903-573_*1108del](/variant/abcd3-c-1903-minus-573-star-1108del).

### 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 3645578). 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.*