Is ABCD1 p.Ser606Leu (c.1817C>T) pathogenic?

ABCD1 p.Ser606Leu (c.1817C>T) is classified Pathogenic in ABCD1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-04-27). AlphaMissense: likely pathogenic (0.9828); Very rare (popmax 0.000112%, nfe); Associated with ABCD1-related disorder.

What condition is associated with ABCD1 p.Ser606Leu (c.1817C>T)?

ABCD1 p.Ser606Leu (c.1817C>T) is associated with ABCD1-related disorder, chronic primary adrenal insufficiency, adrenoleukodystrophy (ClinVar).

How common is ABCD1 p.Ser606Leu (c.1817C>T) in the general population?

ABCD1 p.Ser606Leu (c.1817C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about ABCD1 p.Ser606Leu (c.1817C>T)?

AlphaMissense predicts likely pathogenic (score 0.9828) — an in-silico prediction, not a clinical call.

ABCD1 p.Ser606Leu

c.1817C>T · rs128624225 · VCV11310

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCD1-related disorder

ClinGen expert panel — Peroxisomal Disorders VCEP

Pathogenic for adrenoleukodystrophy. Applied ACMG criteria (verbatim):

PP4_Moderate PP1_Strong PM2_Supporting PS3_Supporting PS4_strong PP3

Curation rationale (ClinGen, verbatim)

The c.1817C>T (p.Ser606Leu) (NM_000033.4) is a missense variant in exon 8 of the ABCD1 gene just upstream of the Walker B domain, which is a well-established mutational hot spot. At least one patient with this variant displayed adrenomyeloneuropathy and adrenal insufficiency, positive family history and elevated VLCFA levels, which is highly specific for adrenoleukodystrophy (PP4_Moderate, PMID: 31526374). The variant has been reported to segregate with adrenoleukodystrophy in ≥3 affected meioses from 1 or more families (PP1_strong; PMID: 8773611). This variant has been reported in 10 probands meeting PP4_Supporting phenotype criteria (PS4_strong; PMIDs: 34826210, 16087056, 15811009, 12624723, 11748843, 10190819, 7668254, 7581394, 8040304). This variant is absent from gnomAD v4.1 (PM2_Supporting). Beta-oxidation assay in ALD patient fibroblasts transfected with the variant showed reduced activity indicating that this variant impact protein function although reduction did not reach ≤26% of WT( PMID: 21476988, 17542813), however it showed lower expression, and was degraded by proteasomes (PS3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for X-linked adrenoleukodystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Peroxisomal VCEP: PP1_strong, PS4, PP4_moderate, PP3, PM2_supporting, PS3_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	0.9828	likely pathogenic ✓ concordant with ClinVar · top 9% in ABCD1
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -13.68	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 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 3,261 bp · p 4e-11 · regional, not allelic
Overall
CADD	25.0	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 0.000112% European (non-Finnish) · 1/890,385 alleles

Overall 0.000888% 1/112,628 alleles · very 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.Ser606Leu
Coding: c.1817C>T
MANE Select: NM_000033
dbSNP: rs128624225
Type: single nucleotide variant
Location: chrX:153743023 (GRCh38)
Structure: AlphaFold pLDDT 81.58 · 14 PDB
Residue 606: a UniProt-annotated variant site (in ald; decreased atp-binding affinity); a UniProt-annotated variant site (in ald; uncertain significance; cald, amn and almd-types); the abc transporter domain

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

Disease context

ABCD1-related disorder

Also linked: chronic primary adrenal insufficiency adrenoleukodystrophy

Similar variants

ABCD1 p.Ser606Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCD1 p.Ser606= 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

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-ser606leu (accessed [today's date]).

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