Is ABCD1 p.Arg418Gln (c.1253G>A) pathogenic?

ABCD1 p.Arg418Gln (c.1253G>A) is classified Conflicting classifications of pathogenicity in ABCD1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-18). AlphaMissense: likely pathogenic (0.6858); Very rare (popmax 0.000223%, nfe); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Arg418Gln (c.1253G>A)?

ABCD1 p.Arg418Gln (c.1253G>A) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Arg418Gln (c.1253G>A) in the general population?

ABCD1 p.Arg418Gln (c.1253G>A) is very rare (popmax 0.000223%, 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.Arg418Gln (c.1253G>A)?

AlphaMissense predicts likely pathogenic (score 0.6858) — an in-silico prediction, not a clinical call.

ABCD1 p.Arg418Gln

c.1253G>A · rs1046633404 · VCV853717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.6858	likely pathogenic
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -12.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 14 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	27.9	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 0.000223% European (non-Finnish) · 2/895,568 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000273% 3/1,098,147 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00214%	46,836
European (non-Finnish)grpmax	0.000223%	447,784

Finnish 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.Arg418Gln
Coding: c.1253G>A
MANE Select: NM_000033
dbSNP: rs1046633404
Type: single nucleotide variant
Location: chrX:153736373 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 418: an α-helix; a UniProt-annotated variant site (in ald; amn-type)

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.Arg418Trp Pathogenic/Likely pathogenic ★★ same residue
ABCD1 p.Arg418Gly Likely 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-arg418gln (accessed [today's date]).

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