ABCD1 c.900+2T>C
ClinGen expert panel — Peroxisomal Disorders VCEP
Likely Pathogenic for adrenoleukodystrophy. Applied ACMG criteria (verbatim):
PVS1_Strong PM2_Supporting PS1_Moderate
Curation rationale (ClinGen, verbatim)
The NM_000033.4:c.900+2T>C variant in ABCD1 occurs within the canonical splice donor site (+2) of intron 1. It is predicted to cause skipping of biologically-relevant-exon 1, resulting in an in-frame deletion (removes amino acids 1-300). However, it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). A different single nucleotide variant (c.900+2T>A) in the same canonical splice dinucleotide, expected to cause skipping of exon 1 (PMID 36180238), is classified as likely pathogenic for X-linked adrenoleukodystrophy by the ClinGen Peroxisomal Disorders VCEP (PS1_Moderate). This variant is absent from gnomADv4.1, gnomAD v3.1.2 and v.2.1.1 and therefore meets the criteria for PM2 Supporting (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked adrenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal VCEP: PVS1_Strong, PS1_Moderate, PM2_Supporting. (ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Consequence | canonical splice-site (±1/±2) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| Splicing | ||
| Splice region | donor +2 | canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone |
| SpliceAI | Δ0.96 | donor loss · deltas |
| Pangolin | Δ0.79 | loss · gain 0.23 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.7 | GERP 1.7, phastCons 1 |
| Non-coding constraint | — | not assessed · autosomes only, so chrX has no window · absence ≠ unconstrained |
| Overall | ||
| CADD | 29.6 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No allele count reported in gnomAD v4.1 (AN 1,130,523). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- ABCD1
- Coding
- c.900+2T>C
- MANE Select
- NM_000033
- dbSNP
- rs2091712381
- Type
- single nucleotide variant
- Location
- chrX:153726168 (GRCh38)
- Structure
- AlphaFold pLDDT 81.58 · 14 PDB
Disease context
adrenoleukodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor X-linked adrenoleukodystrophy (Orphanet):
- Inheritance
- X-linked dominant
- Onset
- Adolescent, Adult, Childhood, Elderly
- Prevalence
- 1-9 / 1 000 000 (Israel)
Similar variants
- ABCD1 c.1635-2A>G Pathogenic ★★ same condition
- ABCD1 c.1781-1G>C Pathogenic ★★ same condition
- ABCD1 c.1781-1G>T Pathogenic/Likely pathogenic ★★ same condition
- ABCD1 c.1866-10G>A Pathogenic/Likely pathogenic ★★ same condition
- ABCD1 c.1866-1G>C Likely pathogenic ★★ same condition
- ABCD1 c.1866-2A>T Likely pathogenic ★★ same condition
- ABCD1 c.901-1G>A Pathogenic ★★ same condition
- ABCD1 c.901-5C>A Likely pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abcd1-c-900-plus-2t-c (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown