Is ABCD1 p.Arg231Gln (c.692G>A) pathogenic?

ABCD1 p.Arg231Gln (c.692G>A) is classified Conflicting classifications of pathogenicity in ABCD1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0741); Ultra-rare (popmax 0.0175%, sas); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Arg231Gln (c.692G>A)?

ABCD1 p.Arg231Gln (c.692G>A) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Arg231Gln (c.692G>A) in the general population?

ABCD1 p.Arg231Gln (c.692G>A) is ultra-rare (popmax 0.0175%, sas) (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.Arg231Gln (c.692G>A)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

ABCD1 p.Arg231Gln

c.692G>A · rs782143050 · VCV1140271

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adrenoleukodystrophy

ClinGen expert panel — Peroxisomal Disorders VCEP

Likely Benign for adrenoleukodystrophy. Applied ACMG criteria (verbatim):

BS1 BP4

Curation rationale (ClinGen, verbatim)

The NM_000033.4:c.692G>A variant in ABCD1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 231 (p.Arg231Gln). The GrpMax filtering allele frequency of the c.692G>A variant in ABCD1 is 0.00009439 in the South Asian population in gnomAD v4.1, which is higher than the ClinGen Peroxisomal Disorders VCEP threshold of ≥0.000017 for BS1, and therefore meets this criterion (BS1). In addition, the computational predictor REVEL gives a score of 0.357 which is below the threshold of 0.5, and the splice predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ABCD1 (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for adenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal Disorders VCEP: BS1, BP4. (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
AlphaMissense	0.0741	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -4.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2.5, phastCons 0.81
Regional constraint	o/e 0.94	unconstrained · MANE · 865 bp · p 0.3 · regional, not allelic
Overall
CADD	9.929	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 0.0175% South Asian · 10/56,994 alleles

Filtering AF 0.00944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00724%

Overall 0.00116% 14/1,209,255 alleles · ultra-rare exomes 12/1,095,632 · genomes 2/113,623 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0175%	5,699
Remaining individualsnot grpmax-eligible	0.0021%	47,593
African / African-American	0.00173%	57,735
European (non-Finnish)	0.000223%	447,734

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.Arg231Gln
Coding: c.692G>A
MANE Select: NM_000033
dbSNP: rs782143050
Type: single nucleotide variant
Location: chrX:153725958 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 231: an α-helix; the abc transmembrane type-1 domain

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.Arg231Trp Benign/Likely benign ★★ same residue
ABCD1 p.Arg231Leu 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-arg231gln (accessed [today's date]).

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