Is ABCD1 p.Lys696Met (c.2087A>T) pathogenic?

ABCD1 p.Lys696Met (c.2087A>T) is classified Conflicting classifications of pathogenicity in ABCD1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-17). AlphaMissense: likely pathogenic (0.8071); Ultra-rare (popmax 0.0321%, mid); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Lys696Met (c.2087A>T)?

ABCD1 p.Lys696Met (c.2087A>T) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Lys696Met (c.2087A>T) in the general population?

ABCD1 p.Lys696Met (c.2087A>T) is ultra-rare (popmax 0.0321%, 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.Lys696Met (c.2087A>T)?

AlphaMissense predicts likely pathogenic (score 0.8071) — an in-silico prediction, not a clinical call.

ABCD1 p.Lys696Met

c.2087A>T · rs782157913 · VCV1027437

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0321%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.8071	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -12.38	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 6.8	GERP 0.78, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 242 bp · p 0.011 · regional, not allelic
Overall
CADD	25.1	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 0.0321% Middle Eastern · 1/3,120 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.0114% 137/1,197,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0321%	3,120
European (non-Finnish)	0.0151%	6,637
Remaining individualsnot grpmax-eligible	0.00425%	23,508

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.Lys696Met
Coding: c.2087A>T
MANE Select: NM_000033
dbSNP: rs782157913
Type: single nucleotide variant
Location: chrX:153743584 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 696: the 'required for homodimerization' region; an α-helix; 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.Lys696= 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
ABCD1 c.901-1G>A 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-lys696met (accessed [today's date]).

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