Is ABCD1 p.Val583Ala (c.1748T>C) pathogenic?

ABCD1 p.Val583Ala (c.1748T>C) is classified Conflicting classifications of pathogenicity in ABCD1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-05). AlphaMissense: likely pathogenic (0.6259); Ultra-rare (popmax 0.0322%, mid); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Val583Ala (c.1748T>C)?

ABCD1 p.Val583Ala (c.1748T>C) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Val583Ala (c.1748T>C) in the general population?

ABCD1 p.Val583Ala (c.1748T>C) is ultra-rare (popmax 0.0322%, mid) (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.Val583Ala (c.1748T>C)?

AlphaMissense predicts likely pathogenic (score 0.6259) — an in-silico prediction, not a clinical call.

ABCD1 p.Val583Ala

c.1748T>C · rs79383557 · VCV2203438

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6259 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0322%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.6259	likely pathogenic
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -11.53	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 3,261 bp · p 4e-11 · 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 0.0322% Middle Eastern · 1/3,110 alleles

Filtering AF 0.00206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.00943% 114/1,209,082 alleles · ultra-rare exomes 93/1,096,395 · genomes 21/112,687 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.18%	555
Middle Easterngrpmax	0.0322%	3,110
Remaining individualsnot grpmax-eligible	0.00421%	23,751
European (non-Finnish)	0.00302%	33,155

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.Val583Ala
Coding: c.1748T>C
MANE Select: NM_000033
dbSNP: rs79383557
Type: single nucleotide variant
Location: chrX:153740687 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 583: the abc transporter 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.Val583Leu Uncertain significance ★★ ⚠ same residue
ABCD1 p.Val583Glu Benign/Likely benign ★★ 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-val583ala (accessed [today's date]).

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