Is ABCD1 p.Phe681Leu (c.2043C>G) pathogenic?

ABCD1 p.Phe681Leu (c.2043C>G) is classified Likely benign in ABCD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.8863); Ultra-rare (popmax 0.0567%, eas); Associated with Inborn genetic diseases.

What condition is associated with ABCD1 p.Phe681Leu (c.2043C>G)?

ABCD1 p.Phe681Leu (c.2043C>G) is associated with Inborn genetic diseases, adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Phe681Leu (c.2043C>G) in the general population?

ABCD1 p.Phe681Leu (c.2043C>G) is ultra-rare (popmax 0.0567%, eas) (gnomAD).

What do computational predictors say about ABCD1 p.Phe681Leu (c.2043C>G)?

AlphaMissense predicts likely pathogenic (score 0.8863) — an in-silico prediction, not a clinical call.

ABCD1 p.Phe681Leu

c.2043C>G · rs782327280 · VCV669027

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

ClinGen expert panel — Peroxisomal Disorders VCEP

Benign for adrenoleukodystrophy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

Evidence Summary: The c.2043C>G (NM_000033.4) variant in ABCD1 is a variant occurring in exon 10. The GrpMax filtering allele frequency in gnomAD v4.1 is 0.0003710 (19/33487 alleles) in the East Asian population with 6 hemizygotes, which is higher than the ClinGen Peroxisomal Disorders threshold (≥0.017% (0.00017)) for BA1. In summary, this variant meets the criteria to be classified as benign for adrenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal Disorders Variant Curation Expert Panel: BA1 (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	0.8863	likely pathogenic
REVEL	0.638	indeterminate
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -4.8	GERP -3.2
Regional constraint	o/e 0.70	unconstrained · MANE · 242 bp · p 0.011 · regional, not allelic
Overall
CADD	4.231	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 0.0567% East Asian · 19/33,487 alleles

Filtering AF 0.0371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0309%

Overall 0.00158% 19/1,201,576 alleles · ultra-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.Phe681Leu
Coding: c.2043C>G
dbSNP: rs782327280
Type: single nucleotide variant
Location: chrX:153743540 (GRCh38)

Full ABCD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adrenoleukodystrophy

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-phe681leu (accessed [today's date]).

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