# NM_139058.3(ARX):c.1337dup (p.Pro447fs)

https://sugi.bio/variant/arx-p-pro447fs

## Summary

**ARX p.Pro447fs (c.1337dup)** is classified **Pathogenic** in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2013-02-08). No gnomAD frequency available for this variant; Associated with X-linked lissencephaly with abnormal genitalia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs797045291 · 1 submitter · 1 linked condition · 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 X-linked lissencephaly with abnormal genitalia.

*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/0012491/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.Pro447fs |
| Coding change (HGVS c.) | c.1337dup |
| MANE Select transcript | [NM_139058](https://www.ncbi.nlm.nih.gov/nuccore/NM_139058) |
| dbSNP | [rs797045291](https://www.ncbi.nlm.nih.gov/snp/rs797045291/) |
| Variant type | Duplication |
| Location | chrX:25007221-25007222 (GRCh38) |
| ClinVar | [VCV210319](https://www.ncbi.nlm.nih.gov/clinvar/variation/210319/) |

**All HGVS expressions:** `NC_000023.10:g.25025340dup`, `NC_000023.11:g.25007223dup`, `NG_008281.1:g.13727dup`, `NM_139058.3:c.1337dup`

## 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 0.586, GERP 0.147, phastCons 0.997 — weakly conserved position
- 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 exon 4 of 5**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((GCG)n). The alignment of this duplication is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- 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 2013-02-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2013-02-08 |

## Associated conditions {#conditions}

[X-linked lissencephaly with abnormal genitalia](https://sugi.bio/atlas/disease/x-linked-lissencephaly-with-abnormal-genitalia/).

**Reported phenotype names (ClinVar):** X-linked lissencephaly with abnormal genitalia.

## Similar variants {#similar}

Related ARX variant pages (same residue, condition, or type): [ARX p.Gly397fs](/variant/arx-p-gly397fs), [ARX c.1120-82_1469dup](/variant/arx-c-1120-minus-82-1469dup), [ARX c.1449-82_1469dup](/variant/arx-c-1449-minus-82-1469dup), [ARX p.Ala275fs](/variant/arx-p-ala275fs), [ARX p.Glu137fs](/variant/arx-p-glu137fs), [ARX p.Gly143_Ala154dup](/variant/arx-p-gly143-ala154dup), [ARX p.Leu324fs](/variant/arx-p-leu324fs), [ARX p.Pro187fs](/variant/arx-p-pro187fs).

### 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 210319). 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.*