Is ABCD1 p.Arg113His (c.338G>A) pathogenic?

ABCD1 p.Arg113His (c.338G>A) is classified Uncertain significance in ABCD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-01). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.00173%, afr); Associated with adrenoleukodystrophy.

What condition is associated with ABCD1 p.Arg113His (c.338G>A)?

ABCD1 p.Arg113His (c.338G>A) is associated with adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Arg113His (c.338G>A) in the general population?

ABCD1 p.Arg113His (c.338G>A) is very rare (popmax 0.00173%, 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.Arg113His (c.338G>A)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

ABCD1 p.Arg113His

c.338G>A · rs1322406234 · VCV1210346

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adrenoleukodystrophy

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -6.51	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 7.5	GERP 0.59, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 865 bp · p 0.3 · regional, not allelic
Overall
CADD	21.4	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 0.00173% African / African-American · 1/57,903 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000459% 5/1,089,169 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00423%	23,644
African / African-Americangrpmax	0.00173%	57,903
European (non-Finnish)	0.000224%	445,665

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg113His
Coding: c.338G>A
MANE Select: NM_000033
dbSNP: rs1322406234
Type: single nucleotide variant
Location: chrX:153725604 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 113: a β-strand; a UniProt-annotated variant site (in ald); the abc transmembrane type-1 domain; the 'interaction with pex19' region

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.Arg113Pro Likely pathogenic ★★ same residue
ABCD1 p.Arg113Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCD1 p.Arg113Leu Uncertain significance ★ ⚠ 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-arg113his (accessed [today's date]).

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