# NM_139058.3(ARX):c.1559del (p.Pro520fs)

https://sugi.bio/variant/arx-p-pro520fs

## Summary

**ARX p.Pro520fs (c.1559del)** is classified **Pathogenic** in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). No gnomAD frequency available for this variant; Associated with developmental and epileptic encephalopathy, 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2519099293 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ARX gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked dominant |
| Diagnostic panels | ARX is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Infantile epileptic spasms syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myoclonus — Very frequent (99-80%)
- Developmental regression — Very frequent (99-80%)
- Hypsarrhythmia — Very frequent (99-80%)
- Infantile spasms — Very frequent (99-80%)
- Abnormality of the nervous system — Frequent (79-30%)
- Abnormal skin morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015298/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ARX](https://sugi.bio/atlas/gene/ARX/) |
| Protein change (HGVS p.) | p.Pro520fs |
| Coding change (HGVS c.) | c.1559del |
| MANE Select transcript | [NM_139058](https://www.ncbi.nlm.nih.gov/nuccore/NM_139058) |
| dbSNP | [rs2519099293](https://www.ncbi.nlm.nih.gov/snp/rs2519099293/) |
| Variant type | Deletion |
| Location | chrX:25004800-25004800 (GRCh38) |
| ClinVar | [VCV2943777](https://www.ncbi.nlm.nih.gov/clinvar/variation/2943777/) |

**All HGVS expressions:** `NC_000023.10:g.25022919del`, `NC_000023.11:g.25004802del`, `NG_008281.1:g.16149del`, `NG_146804.1:g.265del`, `NM_139058.3:c.1559del`

## 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 -0.672, GERP -1.06, phastCons 0.011 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (5 of 5)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ARX** 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):

- **genetic developmental and epileptic encephalopathy** — Definitive (XL)
- **X-linked complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 56.51, 11% of residues very-high.

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

*Describes the biological roles of ARX (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:** ARX's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding.


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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, sequence-specific double-stranded DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of transcription by RNA polymerase II, intestinal type G enteroendocrine cell differentiation, intestinal type I enteroendocrine cell differentiation, intestinal type L enteroendocrine cell differentiation, intestinal type N enteroendocrine cell differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-15 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 1](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-1/), [intellectual disability, X-linked, with or without seizures, ARX-related](https://sugi.bio/atlas/disease/intellectual-disability-x-linked-with-or-without-seizures-arx-related/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 1, Intellectual disability, X-linked, with or without seizures, ARX-related, X-linked infantile spasms, West's syndrome, Tonic spasms with clustering, arrest of psychomotor development and hypsarrhythmia on EEG, X-Linked Infantile Spasm Syndrome, OHTAHARA SYNDROME, X-LINKED, INFANTILE SPASM SYNDROME, X-LINKED 1, Epileptic encephalopathy, early infantile, 1, Mental retardation, X-linked 52.

## Similar variants {#similar}

Related ARX variant pages (same residue, condition, or type): [ARX p.Pro520Arg](/variant/arx-p-pro520arg), [ARX p.Gly120fs](/variant/arx-p-gly120fs), [ARX p.Leu491fs](/variant/arx-p-leu491fs), [ARX p.Pro490_Leu491insTer](/variant/arx-p-pro490-leu491inster), [ARX p.240EEELLEDD[1]](/variant/arx-p-240eeelledd-1), [ARX p.Ala110_Ala115del](/variant/arx-p-ala110-ala115del), [ARX p.Asp140_Ala151del](/variant/arx-p-asp140-ala151del), [ARX p.Ala148_Ala155del](/variant/arx-p-ala148-ala155del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2943777). 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.*