# NM_000489.6(ATRX):c.1974T>G (p.Arg658=)

https://sugi.bio/variant/atrx-p-arg658

## Summary

**ATRX p.Arg658= (c.1974T>G)** is classified **Conflicting classifications of pathogenicity** in ATRX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-04-06). Very rare (popmax 0.000112%, nfe); Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1603222314 · 2 submitters · 2 linked conditions · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the ATRX gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to intellectual disability-hypotonic facies syndrome, X-linked, 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003521/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATRX](https://sugi.bio/atlas/gene/ATRX/) |
| Protein change (HGVS p.) | p.Arg658= |
| Coding change (HGVS c.) | c.1974T>G |
| MANE Select transcript | [NM_000489](https://www.ncbi.nlm.nih.gov/nuccore/NM_000489) |
| dbSNP | [rs1603222314](https://www.ncbi.nlm.nih.gov/snp/rs1603222314/) |
| Variant type | single nucleotide variant |
| Location | chrX:77683282-77683282 (GRCh38) |
| ClinVar | [VCV699023](https://www.ncbi.nlm.nih.gov/clinvar/variation/699023/) |

**All HGVS expressions:** `LRG_1153:g.107988T>G`, `NC_000023.10:g.76938774A>C`, `NC_000023.11:g.77683282A>C`, `NG_008838.3:g.107988T>G`, `NM_000489.6:c.1974T>G`, `NM_138270.5:c.1860T>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.357, GERP -4.4, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 7.484**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/894,575 in the highest group · 1/1,097,006 alleles overall — very rare (popmax 0.000112%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ATRX** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ATR-X-related syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **658** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 52.40, 6% of residues very-high.

**13 experimental structure(s)** (PDB): [2JM1](https://www.rcsb.org/structure/2JM1), [2LBM](https://www.rcsb.org/structure/2LBM), [2LD1](https://www.rcsb.org/structure/2LD1), [3QL9](https://www.rcsb.org/structure/3QL9), [3QLA](https://www.rcsb.org/structure/3QLA), [3QLC](https://www.rcsb.org/structure/3QLC).

## What this gene does {#gene-function}

*Describes the biological roles of ATRX (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ATRX's established molecular role includes chromatin binding. p.Arg658= falls in the disordered region. In Reactome, ATRX is annotated in disease pathway(s) including **Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations**, **Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations**.

**Disease mechanism (Reactome):** ATRX loss or alteration is curated in [Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations](https://reactome.org/content/detail/R-HSA-9670615), [Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations](https://reactome.org/content/detail/R-HSA-9670613).

### Pathways affected {#pathways}

ATRX participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations](https://reactome.org/content/detail/R-HSA-9670615) | curated |
| ⚕ [Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations](https://reactome.org/content/detail/R-HSA-9670613) | curated |
| [Inhibition of DNA recombination at telomere](https://reactome.org/content/detail/R-HSA-9670095) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** chromatin binding, DNA translocase activity, histone binding, histone H3K9me2/3 reader activity, chromo shadow domain binding.

**Biological process:** chromatin organization, nucleosome assembly, chromatin remodeling, subtelomeric heterochromatin formation, positive regulation of transcription by RNA polymerase II, negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-04-06.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Uncertain significance | criteria provided, single submitter | curation | 2022-05-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-06 |

## Associated conditions {#conditions}

[intellectual disability-hypotonic facies syndrome, X-linked, 1](https://sugi.bio/atlas/disease/intellectual-disability-hypotonic-facies-syndrome-x-linked-1/), [alpha thalassemia-X-linked intellectual disability syndrome](https://sugi.bio/atlas/disease/alpha-thalassemia-x-linked-intellectual-disability-syndrome/).

**Reported phenotype names (ClinVar):** Intellectual disability-hypotonic facies syndrome, X-linked, 1, Alpha thalassemia-X-linked intellectual disability syndrome, XLMR-HYPOTONIC FACIES SYNDROME, X-linked intellectual disability-hypotonic face syndrome, Smith Fineman Myers syndrome 1, HOLMES-GANG SYNDROME, CHUDLEY-LOWRY SYNDROME, Chudley syndrome 1, Chudley-Lowry-Hoar syndrome, Carpenter-Waziri syndrome.

## Similar variants {#similar}

Related ATRX variant pages (same residue, condition, or type): [ATRX p.Arg658His](/variant/atrx-p-arg658his), [ATRX p.Arg658Cys](/variant/atrx-p-arg658cys), [ATRX c.5449-7A>G](/variant/atrx-c-5449-minus-7a-g), [ATRX p.Arg1022Ter](/variant/atrx-p-arg1022ter), [ATRX p.Arg1661Cys](/variant/atrx-p-arg1661cys), [ATRX p.Arg2085Cys](/variant/atrx-p-arg2085cys), [ATRX p.Arg2085His](/variant/atrx-p-arg2085his), [ATRX p.Arg2131Gln](/variant/atrx-p-arg2131gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 699023). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*