Is ABCD1 p.Arg80Trp (c.238C>T) pathogenic?

ABCD1 p.Arg80Trp (c.238C>T) is classified Uncertain significance in ABCD1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-13). AlphaMissense: likely benign (0.1862); Very rare (popmax 0.000115%, nfe); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Arg80Trp (c.238C>T)?

ABCD1 p.Arg80Trp (c.238C>T) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Arg80Trp (c.238C>T) in the general population?

ABCD1 p.Arg80Trp (c.238C>T) is very rare (popmax 0.000115%, nfe) (gnomAD).

How is X-linked adrenoleukodystrophy inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCD1 p.Arg80Trp (c.238C>T)?

AlphaMissense predicts likely benign (score 0.1862) — an in-silico prediction, not a clinical call.

ABCD1 p.Arg80Trp

c.238C>T · rs868977355 · VCV528336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000115%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.1862	likely benign
REVEL	0.769	pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 865 bp · p 0.3 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000115% European (non-Finnish) · 1/871,561 alleles

Overall 9.53e-05% 1/1,049,804 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCD1
Protein: p.Arg80Trp
Coding: c.238C>T
MANE Select: NM_000033
dbSNP: rs868977355
Type: single nucleotide variant
Location: chrX:153725504 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 80: an α-helix; the 'interaction with pex19' region; the 'pex19 binding site and required for peroxisomal targeting' region

Full ABCD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

adrenoleukodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked adrenoleukodystrophy (Orphanet):

Inheritance: X-linked dominant
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-9 / 1 000 000 (Israel)

Similar variants

ABCD1 p.Arg80_Leu82del Pathogenic/Likely pathogenic ★★ same residue
ABCD1 p.Arg80_Leu82dup Pathogenic ★★ same residue
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

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-p-arg80trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown