# NM_000489.6(ATRX):c.5722G>T (p.Asp1908Tyr)

https://sugi.bio/variant/atrx-p-asp1908tyr

## Summary

**ATRX p.Asp1908Tyr (c.5722G>T)** is classified **Uncertain significance** in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2016-04-15). AlphaMissense: likely pathogenic (0.9662); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1057522290 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ATRX gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [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.Asp1908Tyr |
| Coding change (HGVS c.) | c.5722G>T |
| MANE Select transcript | [NM_000489](https://www.ncbi.nlm.nih.gov/nuccore/NM_000489) |
| dbSNP | [rs1057522290](https://www.ncbi.nlm.nih.gov/snp/rs1057522290/) |
| Variant type | single nucleotide variant |
| Location | chrX:77599796-77599796 (GRCh38) |
| ClinVar | [VCV385652](https://www.ncbi.nlm.nih.gov/clinvar/variation/385652/) |

**All HGVS expressions:** `LRG_1153:g.191474G>T`, `NC_000023.10:g.76855265C>A`, `NC_000023.11:g.77599796C>A`, `NG_008838.3:g.191474G>T`, `NM_000489.6:c.5722G>T`, `NM_138270.5:c.5608G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9662)
- REVEL 0.689 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.495 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.603, GERP 2.62, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.6**. 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.*
- Regional missense constraint: **o/e 0.14** across the covering region of the MANE Select transcript (77,599,772–77,600,537), spanning 765 bp — the region is depleted of missense variation. Chi-square p 2.1e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.38**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.38**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.46** (loss), gain 0.02 / loss 0.46. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2016-04-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-04-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ATRX variant pages (same residue, condition, or type): [ATRX c.134-2A>G](/variant/atrx-c-134-minus-2a-g), [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), [ATRX p.Arg2178Trp](/variant/atrx-p-arg2178trp).

### 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 385652). 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.*