Is ABCD1 p.Ser342Pro (c.1024T>C) pathogenic?

ABCD1 p.Ser342Pro (c.1024T>C) is classified Conflicting classifications of pathogenicity in ABCD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.9561); Absent from gnomAD v4.1; Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Ser342Pro (c.1024T>C)?

ABCD1 p.Ser342Pro (c.1024T>C) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Ser342Pro (c.1024T>C) in the general population?

ABCD1 p.Ser342Pro (c.1024T>C) 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.

What do computational predictors say about ABCD1 p.Ser342Pro (c.1024T>C)?

AlphaMissense predicts likely pathogenic (score 0.9561) — an in-silico prediction, not a clinical call.

ABCD1 p.Ser342Pro

c.1024T>C · VCV4710906

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9561 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adrenoleukodystrophy

ClinGen expert panel — Peroxisomal Disorders VCEP

Likely Pathogenic for adrenoleukodystrophy. Applied ACMG criteria (verbatim):

PP4_Moderate PM2_Supporting PS3_Supporting PP1 PP3

Curation rationale (ClinGen, verbatim)

The NM_000033.4(ABCD1):c.1024T>C variant in ABCD1 is a missense variant predicted to cause the substitution of serine by proline at amino acid 342 (p.Ser342Pro). This missense variant occurs in exon 2 and is part of the transmembrane domain 6 of the ABCD1 protein. At least one individual with this variant meets phenotype criteria at the moderate strength, with evidence of adrenomyeloneuropathy, elevated VLCFAs, and a positive family history (PP4_Moderate, internal lab contribution). The variant has been reported to segregate with ABCD1 deficiency in 1 affected family member from 1 family (PP1; Internal lab contribution). Beta-oxidation assay with this variant in X-ALD fibroblasts showed absence of restoration of beta-oxidation activity, indicating that this variant impacts protein function even though it was shown to localize to the peroxisome on immunofluorescence assay (PMID: 17542813; PS3_Supporting). This missense variant is completely absent from gnomAD v2.1.1, v3.1.2, and v4 (PM2_Supporting). It has a REVEL score of 0.853, which is above the PP3 threshold (>=0.85) for ABCD1 set by the Peroxisomal VCEP (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked ABCD1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal VCEP: PP4_Moderate, PP3, PP1, PS3_Supporting, PM2_Supporting. (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	0.9561	likely pathogenic
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -10.16	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 5	GERP 0.76, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 14 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	24.8	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

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.Ser342Pro
Coding: c.1024T>C
MANE Select: NM_000033
Type: single nucleotide variant
Location: chrX:153729355 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 342: an α-helix; the abc transmembrane type-1 domain; a UniProt-annotated variant site (in ald; amn-type)

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.Ser342Leu Uncertain significance ★★ ⚠ same residue
ABCD1 p.Ser342Trp Uncertain significance ★★ ⚠ same residue
ABCD1 p.Ser342= 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

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-ser342pro (accessed [today's date]).

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