ATRX

Chr XXLDXLR

ATRX chromatin remodeler

Also known as: JMS, MRX52, RAD54, RAD54L, XH2, XNP, ZNF-HX

NCBI Gene: 546ENSG00000085224UniProt: P46100

The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Alpha-thalassemia myelodysplasia syndrome, somaticMIM #300448
Alpha-thalassemia/impaired intellectual development syndromeMIM #301040
XLD
Intellectual disability-hypotonic facies syndrome, X-linkedMIM #309580
XLR
Alpha-thalassemia/impaired intellectual development syndromeMIM #301040
XLD
493
ClinVar variants
32
Pathogenic / LP
1.00
pLI score· haploinsufficient
6
Active trials
Clinical Summary— ATRX
🧬
Gene-Disease Validity (ClinGen)
ATR-X-related syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 270 VUS of 493 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.12LOEUF
pLI 1.000
Z-score 8.22
OE 0.06 (0.03–0.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.10Z-score
OE missense 0.70 (0.66–0.75)
604 obs / 860.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.03–0.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.66–0.75)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 5 / 88.5Missense obs/exp: 604 / 860.0Syn Z: -0.82

ClinVar Variant Classifications

493 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic13
VUS270
Likely Benign174
Benign16
Conflicting1
19
Pathogenic
13
Likely Pathogenic
270
VUS
174
Likely Benign
16
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
2
16
0
19
Likely Pathogenic
2
10
1
0
13
VUS
1
226
24
19
270
Likely Benign
0
30
69
75
174
Benign
0
2
5
9
16
Conflicting
—1
Total4270115103493

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ATRX · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ATRX-related alpha-thalassemia intellectual developmental disorder syndrome non-deletion type

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Alpha-thalassemia myelodysplasia syndrome, somatic

MIM #300448

Molecular basis of disorder known

Alpha-thalassemia/impaired intellectual development syndrome

MIM #301040

Molecular basis of disorder known

X-linked dominant

Intellectual disability-hypotonic facies syndrome, X-linked

MIM #309580

Molecular basis of disorder known

X-linked recessive

Alpha-thalassemia/impaired intellectual development syndrome

MIM #301040

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — ATRX
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.
Mirabello L et al.·JAMA Oncol
2020Cohort
The genetic landscape of high-risk neuroblastoma.
Pugh TJ et al.·Nat Genet
2013
Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.
Cancer Genome Atlas Research Network et al.·N Engl J Med
2015
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.
Grozeva D et al.·Hum Mutat
2015
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.
Schwartzentruber J et al.·Nature
2012Functional
The expanding phenotypes of cohesinopathies: one ring to rule them all!
Piché J et al.·Cell Cycle
2019Review
A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants.
Ji J et al.·Cold Spring Harb Mol Case Stud
2019
Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.
Calsina B et al.·Nat Commun
2023
Frequency and Clinical Significance of Clonal and Subclonal Driver Mutations in High-Risk Neuroblastoma at Diagnosis: A Children's Oncology Group Study.
Berko ER et al.·J Clin Oncol
2025Clinical trial
Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.
Reinhardt A et al.·Acta Neuropathol
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Altered Brain Structure in an ATRX-Deficient Mouse Model of Autism Spectrum Disorder.
Quesnel K et al.·Autism Res
2026Functional
ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression.
Shen Y et al.·Nat Commun
2026
A case report on the diagnosis and treatment of a glioneuronal tumor with ATRX alteration, kinase fusion, and anaplastic features.
He S et al.·Front Oncol
2026🔓 Open AccessCase report
Alternative Lengthening of Telomeres in Malignant Perivascular Epithelioid Cell Neoplasms: Correlation With Molecular Features Including ATRX Gene Mutation Status.
Lin R et al.·Mod Pathol
2026
SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use Alternative Lengthening of Telomeres.
Brown A et al.·Neuro Oncol
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Pancreatic Neuroendocrine Tumor

ATRX/DAXX in EUS-FNB Specimens of Pan-NETs

ACTIVE NOT RECRUITING
NCT06406387Azienda Ospedaliera Universitaria Integrata VeronaStarted 2024-06-01
ATRX/DAXX immunohistochemistry
Glioma

Clinical Study for the Safety and Therapeutic Efficacy of the AI-QMMM Designed TamavaqTM Personalised Vaccine in Patients With Newly Diagnosed Glioma.

RECRUITING
NCT07077616Phase EARLY_PHASE1Biogenea Pharmaceuticals Ltd.Started 2025-07-01
Biological: personalized vaccine Based on genetic and transcriptional sequencing information, personalized peptide vaccines would be designed and produced;
Neuroendocrine Carcinoma MetastaticPancreatic Tumors

FTT PET/CT in Pancreatic Neuroendocrine Tumors

RECRUITING
NCT07114939Phase PHASE1Abramson Cancer Center at Penn MedicineStarted 2025-10-01
[18F]FluorThanatrace
Small Cell Lung CancerAdvanced Solid Malignant Tumor

Chiauranib for Advanced Solid Malignant Tumors and Relapsed/Refractory SCLC.

RECRUITING
NCT05271292Phase PHASE1, PHASE2Chipscreen Biosciences, Ltd.Started 2022-08-26
Chiauranib
Gastric CancerGastroEsophageal Cancer

Study of SBRT/Olaparib Followed by Pembrolizumab/Olaparib in Gastric Cancers

ACTIVE NOT RECRUITING
NCT05379972Phase PHASE2University of Colorado, DenverStarted 2023-01-12
PembrolizumabOlaparibStereotactic Body Radiation Therapy

External Resources

Links to major genomics databases and tools