# NM_000033.4(ABCD1):c.1966_1967dup (p.Ile657fs)

https://sugi.bio/variant/abcd1-p-ile657fs

## Summary

**ABCD1 p.Ile657fs (c.1966_1967dup)** is classified **Pathogenic** in ABCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2148399303 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ABCD1 gene that is reported as disease-causing, but on limited review, 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 | [ABCD1](https://sugi.bio/atlas/gene/ABCD1/) |
| Protein change (HGVS p.) | p.Ile657fs |
| Coding change (HGVS c.) | c.1966_1967dup |
| MANE Select transcript | [NM_000033](https://www.ncbi.nlm.nih.gov/nuccore/NM_000033) |
| dbSNP | [rs2148399303](https://www.ncbi.nlm.nih.gov/snp/rs2148399303/) |
| Variant type | Microsatellite |
| Location | chrX:153743317-153743318 (GRCh38) |
| ClinVar | [VCV1322475](https://www.ncbi.nlm.nih.gov/clinvar/variation/1322475/) |

**All HGVS expressions:** `LRG_1017:g.23452TC[3]`, `LRG_1017t1:c.1966_1967dup`, `NC_000023.10:g.153008773TC[3]`, `NC_000023.11:g.153743319TC[3]`, `NG_009022.2:g.23452TC[3]`, `NM_000033.4:c.1966_1967dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.757, GERP -3.14, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (9 of 10, 29 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr10:38601341). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ABCD1** population constraint: ClinGen dosage — haploinsufficiency 3, 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):

- **adrenoleukodystrophy** — Definitive (XL)

## Protein context {#protein}

Residue **657** lies in a UniProt-annotated variant site (in ald; cald-type); a β-strand; the abc transporter domain.

AlphaFold model confidence (whole protein): pLDDT 81.58, 43% of residues very-high.

**14 experimental structure(s)** (PDB): [7RR9](https://www.rcsb.org/structure/7RR9), [7RRA](https://www.rcsb.org/structure/7RRA), [7SHM](https://www.rcsb.org/structure/7SHM), [7SHN](https://www.rcsb.org/structure/7SHN), [7VR1](https://www.rcsb.org/structure/7VR1), [7VWC](https://www.rcsb.org/structure/7VWC).

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

*Describes the biological roles of ABCD1 (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:** ABCD1's established molecular role includes long-chain fatty acid transmembrane transporter activity. p.Ile657fs falls in the abc transporter domain. In Reactome, ABCD1 is annotated in disease pathway(s) including **Defective ABCD1 causes ALD**.

**Disease mechanism (Reactome):** ABCD1 loss or alteration is curated in [Defective ABCD1 causes ALD](https://reactome.org/content/detail/R-HSA-5684045).

### Pathways affected {#pathways}

ABCD1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCD1 causes ALD](https://reactome.org/content/detail/R-HSA-5684045) | curated |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [Beta-oxidation of very long chain fatty acids](https://reactome.org/content/detail/R-HSA-390247) | curated |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | curated |
| [Linoleic acid (LA) metabolism](https://reactome.org/content/detail/R-HSA-2046105) | curated |
| [alpha-linolenic acid (ALA) metabolism](https://reactome.org/content/detail/R-HSA-2046106) | curated |

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

**Molecular function:** long-chain fatty acid transmembrane transporter activity, ATP binding, ABC-type fatty-acyl-CoA transporter activity, ATP hydrolysis activity, enzyme binding, ATPase-coupled transmembrane transporter activity.

**Biological process:** very long-chain fatty acid metabolic process, fatty acid beta-oxidation, peroxisome organization, long-chain fatty acid import into peroxisome, positive regulation of fatty acid beta-oxidation, very long-chain fatty-acyl-CoA catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-17 |

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

## Same-residue context {#hotspot}

Residue **657** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCD1 p.Ile657del](/variant/abcd1-p-ile657del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCD1 variant pages (same residue, condition, or type): [ABCD1 p.Ile657del](/variant/abcd1-p-ile657del), [ABCD1 p.Glu292del](/variant/abcd1-p-glu292del), [ABCD1 p.Lys373del](/variant/abcd1-p-lys373del), [ABCD1 p.Leu139del](/variant/abcd1-p-leu139del), [ABCD1 p.Leu197fs](/variant/abcd1-p-leu197fs), [ABCD1 p.Leu670fs](/variant/abcd1-p-leu670fs), [ABCD1 p.Pro143fs](/variant/abcd1-p-pro143fs), [ABCD1 p.Val251del](/variant/abcd1-p-val251del).

### 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 1322475). 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.*