# NM_139058.3(ARX):c.141G>A (p.Ala47=)

https://sugi.bio/variant/arx-p-ala47

## Summary

**ARX p.Ala47= (c.141G>A)** is classified **Likely benign** in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). Very rare (popmax 0.00531%, sas); Associated with developmental and epileptic encephalopathy, 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs767794651 · 1 submitter · 2 linked conditions · very rare (popmax 0.00531%, sas)

## For patients & families {#patients}

This is a change in the ARX gene that is classified as likely benign — not considered disease-causing, 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.Ala47= |
| Coding change (HGVS c.) | c.141G>A |
| MANE Select transcript | [NM_139058](https://www.ncbi.nlm.nih.gov/nuccore/NM_139058) |
| dbSNP | [rs767794651](https://www.ncbi.nlm.nih.gov/snp/rs767794651/) |
| Variant type | single nucleotide variant |
| Location | chrX:25015597-25015597 (GRCh38) |
| ClinVar | [VCV2921562](https://www.ncbi.nlm.nih.gov/clinvar/variation/2921562/) |

**All HGVS expressions:** `NC_000023.10:g.25033714C>T`, `NC_000023.11:g.25015597C>T`, `NG_008281.1:g.5352G>A`, `NM_139058.3:c.141G>A`

## 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 0.046, GERP -1.02, phastCons 0.871 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.04**. 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 (gnomAD v4.1): grpmax **0.00531%** (sas) · FAF95 0.00141% · FAF99 0.000691% · 3/56,482 in the highest group · 3/1,096,358 alleles overall — very rare (popmax 0.00531%, sas).

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-19 |

## 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.Ala47Ser](/variant/arx-p-ala47ser), [ARX p.Ala47Thr](/variant/arx-p-ala47thr), [ARX p.Arg330His](/variant/arx-p-arg330his), [ARX p.Arg332Gly](/variant/arx-p-arg332gly), [ARX p.Arg332His](/variant/arx-p-arg332his), [ARX p.Arg371Gln](/variant/arx-p-arg371gln), [ARX p.Arg371Ter](/variant/arx-p-arg371ter), [ARX p.Arg384Cys](/variant/arx-p-arg384cys).

### 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 2921562). 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.*