# NM_000033.4(ABCD1):c.1660C>A (p.Arg554Ser)

https://sugi.bio/variant/abcd1-p-arg554ser

## Summary

**ABCD1 p.Arg554Ser (c.1660C>A)** is classified **Likely pathogenic** in ABCD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.7183); Absent from gnomAD v4.1; Associated with adrenoleukodystrophy.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs398123104 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCD1 gene that is considered likely disease-causing, submitted by 4 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 |
| Diagnostic panels | ABCD1 is a diagnostic-grade gene on 19 Genomics England panels |

**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.Arg554Ser |
| Coding change (HGVS c.) | c.1660C>A |
| MANE Select transcript | [NM_000033](https://www.ncbi.nlm.nih.gov/nuccore/NM_000033) |
| dbSNP | [rs398123104](https://www.ncbi.nlm.nih.gov/snp/rs398123104/) |
| Variant type | single nucleotide variant |
| Location | chrX:153740599-153740599 (GRCh38) |
| ClinVar | [VCV92319](https://www.ncbi.nlm.nih.gov/clinvar/variation/92319/) |

**All HGVS expressions:** `LRG_1017:g.20732C>A`, `LRG_1017t1:c.1660C>A`, `NC_000023.10:g.153006053C>A`, `NC_000023.11:g.153740599C>A`, `NG_009022.2:g.20732C>A`, `NM_000033.4:c.1660C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7183) — concordant with the pathogenic call
- REVEL 0.925 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.661 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.68) — consistent with the pathogenic call
- Conservation: phyloP 3.993, GERP 1.88, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.5**. 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 0.38** across the covering region of the MANE Select transcript (153,740,228–153,743,489), spanning 3,261 bp. Chi-square p 4e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.68**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.68**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **554** lies in a UniProt-annotated variant site (in ald); an α-helix; 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.Arg554Ser 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-18.

**Submitter consensus:** unanimous (4/4 Likely pathogenic).

**Submission history:** 4 submissions (2015–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-27 |
| Eurofins Ntd Llc (ga) | Likely pathogenic | criteria provided, single submitter | clinical testing | 2015-06-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-18 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-19 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **554** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCD1 p.Arg554His](/variant/abcd1-p-arg554his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCD1 variant pages (same residue, condition, or type): [ABCD1 p.Arg554His](/variant/abcd1-p-arg554his), [ABCD1 p.Arg554Cys](/variant/abcd1-p-arg554cys), [ABCD1 c.1635-2A>G](/variant/abcd1-c-1635-minus-2a-g), [ABCD1 c.1781-1G>C](/variant/abcd1-c-1781-minus-1g-c), [ABCD1 c.1781-1G>T](/variant/abcd1-c-1781-minus-1g-t), [ABCD1 c.1866-10G>A](/variant/abcd1-c-1866-minus-10g-a), [ABCD1 c.1866-1G>C](/variant/abcd1-c-1866-minus-1g-c), [ABCD1 c.1866-2A>T](/variant/abcd1-c-1866-minus-2a-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 92319). 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.*