# NM_139058.3(ARX):c.1555_1556insGG (p.Asp519fs)

https://sugi.bio/variant/arx-p-asp519fs

## Summary

**ARX p.Asp519fs (c.1555_1556insGG)** is classified **Pathogenic** in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-10). No gnomAD frequency available for this variant; Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1601945655 · 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 intellectual disability, X-linked, with or without seizures, ARX-related.

*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/0005614/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.Asp519fs |
| Coding change (HGVS c.) | c.1555_1556insGG |
| MANE Select transcript | [NM_139058](https://www.ncbi.nlm.nih.gov/nuccore/NM_139058) |
| dbSNP | [rs1601945655](https://www.ncbi.nlm.nih.gov/snp/rs1601945655/) |
| Variant type | Insertion |
| Location | chrX:25004803-25004804 (GRCh38) |
| ClinVar | [VCV641421](https://www.ncbi.nlm.nih.gov/clinvar/variation/641421/) |

**All HGVS expressions:** `NC_000023.10:g.25022921_25022922insCC`, `NC_000023.11:g.25004804_25004805insCC`, `NG_008281.1:g.16145_16146insGG`, `NM_139058.3:c.1555_1556insGG`

## 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 5.888, GERP -0.831, phastCons 1 — highly conserved position (PP3-type support)
- 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 insertion 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 3/3, triplosensitivity 0/3. *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 2020-07-10.

**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 | 2020-07-10 |

## Associated conditions {#conditions}

[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/), [developmental and epileptic encephalopathy, 1](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-1/).

**Reported phenotype names (ClinVar):** Intellectual disability, X-linked, with or without seizures, ARX-related, Developmental and epileptic encephalopathy, 1, MENTAL RETARDATION, X-LINKED 29, MENTAL RETARDATION, X-LINKED 32, MENTAL RETARDATION, X-LINKED 33, MENTAL RETARDATION, X-LINKED 38, MENTAL RETARDATION, X-LINKED 43, MENTAL RETARDATION, X-LINKED 76, MENTAL RETARDATION, X-LINKED 87, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 29.

## Similar variants {#similar}

Related ARX variant pages (same residue, condition, or type): [ARX p.Ala155_Trp156insAlaAla](/variant/arx-p-ala155-trp156insalaala), [ARX p.Asp519Ala](/variant/arx-p-asp519ala), [ARX p.Ala105_Ala115dup](/variant/arx-p-ala105-ala115dup), [ARX p.Ala108_Ala115dup](/variant/arx-p-ala108-ala115dup), [ARX p.Ala109_Ala115dup](/variant/arx-p-ala109-ala115dup), [ARX p.Arg330His](/variant/arx-p-arg330his), [ARX p.Arg332Gly](/variant/arx-p-arg332gly), [ARX p.Arg332His](/variant/arx-p-arg332his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 641421). 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.*