# NM_000033.4(ABCD1):c.1440del (p.Ile481fs)

https://sugi.bio/variant/abcd1-p-ile481fs

## Summary

**ABCD1 p.Ile481fs (c.1440del)** is classified **Pathogenic** in ABCD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-11-07). No gnomAD frequency available for this variant; Associated with adrenoleukodystrophy.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1557054318 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ABCD1 gene that is considered disease-causing, submitted by 3 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.Ile481fs |
| Coding change (HGVS c.) | c.1440del |
| dbSNP | [rs1557054318](https://www.ncbi.nlm.nih.gov/snp/rs1557054318/) |
| Variant type | Deletion |
| Location | chrX:153737200-153737200 (GRCh38) |
| ClinVar | [VCV439349](https://www.ncbi.nlm.nih.gov/clinvar/variation/439349/) |

**All HGVS expressions:** `LRG_1017:g.17336del`, `LRG_1017t1:c.1440del`, `NC_000023.10:g.153002657del`, `NC_000023.11:g.153737203del`, `NG_009022.2:g.17336del`, `NM_000033.3:c.1440del`, `NM_000033.4:c.1440del`

## 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 7.875, GERP 1.55, 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.
- 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** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-11-07.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2017–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2017-01-29 |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-08-31 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-07 |

## Associated conditions {#conditions}

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

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

### 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 439349). 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.*