Is ABCD1 p.Arg74Trp (c.220C>T) pathogenic?

ABCD1 p.Arg74Trp (c.220C>T) is classified Likely pathogenic in ABCD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-08). AlphaMissense: ambiguous (0.4702); Very rare (popmax 0.000114%, nfe); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Arg74Trp (c.220C>T)?

ABCD1 p.Arg74Trp (c.220C>T) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Arg74Trp (c.220C>T) in the general population?

ABCD1 p.Arg74Trp (c.220C>T) is very rare (popmax 0.000114%, 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.Arg74Trp (c.220C>T)?

AlphaMissense predicts ambiguous (score 0.4702) — an in-silico prediction, not a clinical call.

ABCD1 p.Arg74Trp

c.220C>T · rs2522264062 · VCV2506019

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000114%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.4702	ambiguous
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -12.85	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.36, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 865 bp · p 0.3 · regional, not allelic
Overall
CADD	23.5	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 0.000114% European (non-Finnish) · 1/874,538 alleles

Overall 0.000189% 2/1,057,852 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00478%	20,899
European (non-Finnish)grpmax	0.000114%	874,539

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg74Trp
Coding: c.220C>T
MANE Select: NM_000033
dbSNP: rs2522264062
Type: single nucleotide variant
Location: chrX:153725486 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 74: 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.Arg74Leu Likely pathogenic ★ same residue
ABCD1 p.Arg74Gln Uncertain significance ★ ⚠ 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-arg74trp (accessed [today's date]).

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