# NM_000489.6(ATRX):c.236C>G (p.Ser79Ter)

https://sugi.bio/variant/atrx-p-ser79ter

## Summary

**ATRX p.Ser79Ter (c.236C>G)** is classified **Pathogenic** in ATRX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2003-08-01). Absent from gnomAD v4.1; Associated with alpha-thalassemia-myelodysplastic syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs122445107 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ATRX gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to alpha-thalassemia-myelodysplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | ATRX is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Alpha-thalassemia-myelodysplastic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thrombocytopenia — Very frequent (99-80%)
- Decreased total neutrophil count — Very frequent (99-80%)
- Microcytic anemia — Very frequent (99-80%)
- HbH hemoglobin — Very frequent (99-80%)
- Fatigue — Very frequent (99-80%)
- Bruising susceptibility — Frequent (79-30%)
- Abnormal bleeding — Frequent (79-30%)
- Dyspnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017167/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.Ser79Ter |
| Coding change (HGVS c.) | c.236C>G |
| MANE Select transcript | [NM_000489](https://www.ncbi.nlm.nih.gov/nuccore/NM_000489) |
| dbSNP | [rs122445107](https://www.ncbi.nlm.nih.gov/snp/rs122445107/) |
| Variant type | single nucleotide variant |
| Location | chrX:77697589-77697589 (GRCh38) |
| ClinVar | [VCV11741](https://www.ncbi.nlm.nih.gov/clinvar/variation/11741/) |

**All HGVS expressions:** `LRG_1153:g.93681C>G`, `NC_000023.10:g.76953077G>C`, `NC_000023.11:g.77697589G>C`, `NG_008838.3:g.93681C>G`, `NM_000489.6:c.236C>G`, `NM_138270.5:c.236C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.53, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 35**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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: **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}

Residue **79** 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.Ser79Ter 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2003-08-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2003-08-01 |

## Associated conditions {#conditions}

[alpha-thalassemia-myelodysplastic syndrome](https://sugi.bio/atlas/disease/alpha-thalassemia-myelodysplastic-syndrome/).

**Reported phenotype names (ClinVar):** Acquired hemoglobin H disease, Alpha-thalassemia-myelodysplastic syndrome, Alpha-thalassemia myelodysplasia syndrome, Alpha-thalassemia myelodysplasia syndrome, somatic.

## Similar variants {#similar}

Related ATRX variant pages (same residue, condition, or type): [ATRX p.Arg246Cys](/variant/atrx-p-arg246cys), [ATRX p.Arg37Ter](/variant/atrx-p-arg37ter), [ATRX p.Tyr1847Cys](/variant/atrx-p-tyr1847cys), [ATRX c.6326+3A>G](/variant/atrx-c-6326-plus-3a-g), [ATRX p.Arg160His](/variant/atrx-p-arg160his), [ATRX p.Gln689Arg](/variant/atrx-p-gln689arg), [ATRX p.Lys1357Arg](/variant/atrx-p-lys1357arg), [ATRX p.Lys796Asn](/variant/atrx-p-lys796asn).

### 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 11741). 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.*