# NM_000033.4(ABCD1):c.1660dup (p.Arg554fs)

https://sugi.bio/variant/abcd1-p-arg554fs

## Summary

**ABCD1 p.Arg554fs (c.1660dup)** is classified **Pathogenic/Likely pathogenic** in ABCD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-18). No gnomAD frequency available for this variant; Associated with adrenoleukodystrophy.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1569541115 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the ABCD1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to adrenoleukodystrophy.

*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) | X-linked dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Prevalence | 1-9 / 1 000 000 (Israel) |
| Clinical trials | 48 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of X-linked adrenoleukodystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of vision — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Visual loss — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Dementia — Very frequent (99-80%)
- Hyperactivity — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005758/index) · [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.Arg554fs |
| Coding change (HGVS c.) | c.1660dup |
| MANE Select transcript | [NM_000033](https://www.ncbi.nlm.nih.gov/nuccore/NM_000033) |
| dbSNP | [rs1569541115](https://www.ncbi.nlm.nih.gov/snp/rs1569541115/) |
| Variant type | Duplication |
| Location | chrX:153740598-153740599 (GRCh38) |
| ClinVar | [VCV576680](https://www.ncbi.nlm.nih.gov/clinvar/variation/576680/) |

**All HGVS expressions:** `LRG_1017:g.20732dup`, `LRG_1017t1:c.1660dup`, `NC_000023.10:g.153006053dup`, `NC_000023.11:g.153740599dup`, `NG_009022.2:g.20732dup`, `NM_000033.3:c.1660dupC`, `NM_000033.4:c.1660dup`

## 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 4.853, GERP -2.13, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- 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.*

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-18.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2018-06-25 |

## Associated conditions {#conditions}

[adrenoleukodystrophy](https://sugi.bio/atlas/disease/adrenoleukodystrophy/).

**Reported phenotype names (ClinVar):** Adrenoleukodystrophy, not provided, ADDISON DISEASE AND CEREBRAL SCLEROSIS, BRONZE SCHILDER DISEASE, SIEMERLING-CREUTZFELDT DISEASE, X-Linked Adrenoleukodystrophy, MELANODERMIC LEUKODYSTROPHY, none provided.

### 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 576680). 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.*