Is ABCD1 p.Trp664Ter (c.1991G>A) pathogenic?

ABCD1 p.Trp664Ter (c.1991G>A) is classified Pathogenic in ABCD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-13). Absent from gnomAD v4.1; Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Trp664Ter (c.1991G>A)?

ABCD1 p.Trp664Ter (c.1991G>A) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Trp664Ter (c.1991G>A) in the general population?

ABCD1 p.Trp664Ter (c.1991G>A) is absent from gnomAD v4.1 (gnomAD).

How is X-linked adrenoleukodystrophy inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

ABCD1 p.Trp664Ter

c.1991G>A · rs2091774163 · VCV872954

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (9 of 10, 0 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Constraint at this position
Conservation	phyloP 9.7	GERP 1.6, phastCons 1
Overall
CADD	50.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCD1
Protein: p.Trp664Ter
Coding: c.1991G>A
MANE Select: NM_000033
dbSNP: rs2091774163
Type: single nucleotide variant
Location: chrX:153743346 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 664: 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.Trp664fs 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
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-trp664ter (accessed [today's date]).

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