Is ABCD1 p.Thr668Pro (c.2002A>C) pathogenic?

ABCD1 p.Thr668Pro (c.2002A>C) is classified Uncertain significance in ABCD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-11-07). AlphaMissense: likely pathogenic (0.8838); Very rare (popmax 0.000112%, nfe); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Thr668Pro (c.2002A>C)?

ABCD1 p.Thr668Pro (c.2002A>C) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Thr668Pro (c.2002A>C) in the general population?

ABCD1 p.Thr668Pro (c.2002A>C) is very rare (popmax 0.000112%, 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.Thr668Pro (c.2002A>C)?

AlphaMissense predicts likely pathogenic (score 0.8838) — an in-silico prediction, not a clinical call.

ABCD1 p.Thr668Pro

c.2002A>C · rs1603236086 · VCV689444

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.8838	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -14.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 242 bp · p 0.011 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/891,761 alleles

Overall 9.17e-05% 1/1,090,770 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.Thr668Pro
Coding: c.2002A>C
dbSNP: rs1603236086
Type: single nucleotide variant
Location: chrX:153743499 (GRCh38)

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)

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-thr668pro (accessed [today's date]).

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