chrX-153726104-C-A

Variant names:

• chrX-153726104-C-A
• rs193922098
• NM_000033.4:c.838C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000033.4(ABCD1):​c.838C>A​(p.Arg280Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000882 in 113,411 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 26)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ABCD1 NM_000033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 10 publications found

Genes affected

ABCD1 (HGNC:61): (ATP binding cassette subfamily D member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. This peroxisomal membrane protein is likely involved in the peroxisomal transport or catabolism of very long chain fatty acids. Defects in this gene have been identified as the underlying cause of adrenoleukodystrophy, an X-chromosome recessively inherited demyelinating disorder of the nervous system. [provided by RefSeq, Jul 2008]

ABCD1 Gene-Disease associations (from GenCC):

• adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• X-linked cerebral adrenoleukodystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary spastic paraplegia

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• adrenomyeloneuropathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000033.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153726105-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 953948.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000033.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	NM_000033.4	MANE Select	c.838C>A	p.Arg280Ser	missense	Exon 1 of 10	NP_000024.2
	ABCD1	NM_001440747.1		c.838C>A	p.Arg280Ser	missense	Exon 1 of 11	NP_001427676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD1	ENST00000218104.6	TSL:1 MANE Select	c.838C>A	p.Arg280Ser	missense	Exon 1 of 10	ENSP00000218104.3
	ABCD1	ENST00000370129.4	TSL:2	c.283C>A	p.Arg95Ser	missense	Exon 1 of 2	ENSP00000359147.3

Frequencies

GnomAD3 genomes AF: 0.00000882 AC: 1 AN: 113357 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000920

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000776 AC: 1 AN: 128935 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1067640 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 342512

African (AFR) AF: 0.00 AC: 0 AN: 25770

American (AMR) AF: 0.00 AC: 0 AN: 31567

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18200

East Asian (EAS) AF: 0.00 AC: 0 AN: 28937

South Asian (SAS) AF: 0.00 AC: 0 AN: 49960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4063

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826449

Other (OTH) AF: 0.00 AC: 0 AN: 44848

GnomAD4 genome AF: 0.00000882 AC: 1 AN: 113411 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 35563

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31332

American (AMR) AF: 0.0000919 AC: 1 AN: 10879

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6337

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53337

Other (OTH) AF: 0.00 AC: 0 AN: 1547

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000842 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 22, 2025

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Gain of phosphorylation at R280 (P = 0.0389)
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922098; hg19: chrX-152991559; COSMIC: COSV54388375; COSMIC: COSV54388375;