# NM_000489.6(ATRX):c.1918G>A (p.Val640Ile)

https://sugi.bio/variant/atrx-p-val640ile

## Summary

**ATRX p.Val640Ile (c.1918G>A)** is classified **Uncertain significance** in ATRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-05). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00296%, eas); Associated with alpha-thalassemia-myelodysplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00296%, eas)

## 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 2 submitters, 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.Val640Ile |
| Coding change (HGVS c.) | c.1918G>A |
| MANE Select transcript | [NM_000489](https://www.ncbi.nlm.nih.gov/nuccore/NM_000489) |
| Variant type | single nucleotide variant |
| Location | chrX:77683338-77683338 (GRCh38) |
| ClinVar | [VCV3598431](https://www.ncbi.nlm.nih.gov/clinvar/variation/3598431/) |

**All HGVS expressions:** `LRG_1153:g.107932G>A`, `LRG_1153t1:c.1918G>A`, `NC_000023.10:g.76938830C>T`, `NC_000023.11:g.77683338C>T`, `NG_008838.3:g.107932G>A`, `NM_000489.6:c.1918G>A`, `NM_138270.5:c.1804G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0685)
- REVEL 0.22 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.562 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.19, GERP -5.29, phastCons 0.004 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.746**. 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 1.31** across the covering region of the MANE Select transcript (77,681,539–77,684,367), spanning 2,828 bp. Chi-square p 3.3e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00296%** (eas) · 1/33,810 in the highest group · 1/1,097,978 alleles overall — very rare (popmax 0.00296%, eas).

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-05.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Acquired hemoglobin H disease, Alpha thalassemia-X-linked intellectual disability syndrome, Intellectual disability-hypotonic facies syndrome, X-linked, 1, Alpha-thalassemia myelodysplasia syndrome, Alpha-thalassemia myelodysplasia syndrome, somatic, Alpha-thalassemia-myelodysplastic syndrome, ATR, NONDELETION TYPE, ATR-X syndrome, Alpha thalassemia mental retardation syndrome, nondeletion type, X-linked, XLMR hypotonic face syndrome.

## Similar variants {#similar}

Related ATRX variant pages (same residue, condition, or type): [ATRX p.Val640Ala](/variant/atrx-p-val640ala), [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 3598431). 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.*