# NM_000033.4(ABCD1):c.922C>T (p.Arg308Cys)

https://sugi.bio/variant/abcd1-p-arg308cys

## Summary

**ABCD1 p.Arg308Cys (c.922C>T)** is classified **Conflicting classifications of pathogenicity** in ABCD1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-29). AlphaMissense: likely benign (0.1067); Ultra-rare (popmax 0.0109%, amr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs782419107 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0109%, amr)

## For patients & families {#patients}

This is a change in the ABCD1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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.Arg308Cys |
| Coding change (HGVS c.) | c.922C>T |
| MANE Select transcript | [NM_000033](https://www.ncbi.nlm.nih.gov/nuccore/NM_000033) |
| dbSNP | [rs782419107](https://www.ncbi.nlm.nih.gov/snp/rs782419107/) |
| Variant type | single nucleotide variant |
| Location | chrX:153729253-153729253 (GRCh38) |
| ClinVar | [VCV850748](https://www.ncbi.nlm.nih.gov/clinvar/variation/850748/) |

**All HGVS expressions:** `LRG_1017:g.9386C>T`, `LRG_1017t1:c.922C>T`, `NC_000023.10:g.152994708C>T`, `NC_000023.11:g.153729253C>T`, `NG_009022.2:g.9386C>T`, `NG_023231.1:g.494G>A`, `NM_000033.4:c.922C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1067)
- REVEL 0.434 (indeterminate)
- SaProt LLR -10.415 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 1.931, GERP -3.45, phastCons 0.986 — weakly conserved position
- CADD: **PHRED 21.8**. 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 0.69** across the covering region of the MANE Select transcript (153,726,133–153,740,227), spanning 14,094 bp. Chi-square p 4.8e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0109%** (amr) · FAF95 0.00426% · FAF99 0.0027% · 5/45,969 in the highest group · 15/1,210,936 alleles overall — ultra-rare (popmax 0.0109%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0109% | 9,194 |
| South Asian | 0.00176% | 56,910 |
| European (non-Finnish) | 0.00101% | 99,485 |

*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 **308** lies in an α-helix; the abc transmembrane type-1 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.Arg308Cys falls in the abc transmembrane type-1 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-29.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-29 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-07-09 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-01 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-17 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [adrenoleukodystrophy](https://sugi.bio/atlas/disease/adrenoleukodystrophy/).

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

## Similar variants {#similar}

Related ABCD1 variant pages (same residue, condition, or type): [ABCD1 p.Arg308Pro](/variant/abcd1-p-arg308pro), [ABCD1 p.Arg308=](/variant/abcd1-p-arg308), [ABCD1 p.Arg308His](/variant/abcd1-p-arg308his), [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).

### 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 850748). 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.*