Is ABCD1 p.Ala19Ser (c.55G>T) pathogenic?

ABCD1 p.Ala19Ser (c.55G>T) is classified Conflicting classifications of pathogenicity in ABCD1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-17). AlphaMissense: likely benign (0.1711); Ultra-rare (popmax 0.018%, afr); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Ala19Ser (c.55G>T)?

ABCD1 p.Ala19Ser (c.55G>T) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Ala19Ser (c.55G>T) in the general population?

ABCD1 p.Ala19Ser (c.55G>T) is ultra-rare (popmax 0.018%, afr) (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.Ala19Ser (c.55G>T)?

AlphaMissense predicts likely benign (score 0.1711) — an in-silico prediction, not a clinical call.

ABCD1 p.Ala19Ser

c.55G>T · rs965462099 · VCV1329074

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1711 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adrenoleukodystrophy

ClinGen expert panel — Peroxisomal Disorders VCEP

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

BS1 BS3_Supporting

Curation rationale (ClinGen, verbatim)

The c.55G>T (NM_000033.4) variant in ABCD1 is a missense variant predicted to cause substitution of alanine by serine at amino acid position 19 (p.Ala19Ser). The filtering allele frequency (the lower threshold of the 95% CI of 8/1038015) of the c.55G>T (p.Ala19Ser) variant in ABCD1 is 0.00007991 for African/African American exomes by gnomAD v4.1, which is higher than the ClinGen Peroxisomal Disorders VCEP threshold (>=0.000017) for BS1, and therefore meets this criterion (BS1). 4 hemizygotes are noted in gnomAD v4.1 for this variant. Beta-oxidation activity assay in X-ALD fibroblasts showed 100% of wild-type levels indicating that this variant does not impact protein function (PMID: 23300730)(BS3_Supporting). The computational predictor REVEL gives a score of 0.612, which is neither above nor below the thresholds predicting a damaging (>=0.85) or benign (<=0.5) impact on ABCD1 function. In summary, this variant meets the criteria to be classified as likely benign for X-linked adrenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal Disorders VCEP: BS1. BS3_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	0.1711	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 865 bp · p 0.3 · regional, not allelic
Overall
CADD	17.23	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 0.018% African / African-American · 10/55,658 alleles

Filtering AF 0.00965% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00739%

Overall 0.00113% 13/1,151,029 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.018%	5,566
Remaining individualsnot grpmax-eligible	0.00442%	22,620
European (non-Finnish)	0.000115%	866,979

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.Ala19Ser
Coding: c.55G>T
MANE Select: NM_000033
dbSNP: rs965462099
Type: single nucleotide variant
Location: chrX:153725321 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB

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.Ala19= 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-ala19ser (accessed [today's date]).

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