Is ABCD1 p.Ala704Val (c.2111C>T) pathogenic?

ABCD1 p.Ala704Val (c.2111C>T) is classified Uncertain significance in ABCD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.1864); Very rare (popmax 0.00175%, afr); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Ala704Val (c.2111C>T)?

ABCD1 p.Ala704Val (c.2111C>T) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Ala704Val (c.2111C>T) in the general population?

ABCD1 p.Ala704Val (c.2111C>T) is very rare (popmax 0.00175%, 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.Ala704Val (c.2111C>T)?

AlphaMissense predicts likely benign (score 0.1864) — an in-silico prediction, not a clinical call.

ABCD1 p.Ala704Val

c.2111C>T · rs782740513 · VCV1391056

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.1864	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -8.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 242 bp · p 0.011 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% African / African-American · 1/57,031 alleles

Filtering AF 0.000388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00028%

Overall 0.000755% 9/1,191,935 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	57,031
European (non-Finnish)	0.000902%	110,874

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.Ala704Val
Coding: c.2111C>T
MANE Select: NM_000033
dbSNP: rs782740513
Type: single nucleotide variant
Location: chrX:153743608 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 704: the 'required for homodimerization' region; a β-strand

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.Ala704= Benign/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-ala704val (accessed [today's date]).

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