# NM_139058.3(ARX):c.639C>T (p.Ser213=)

https://sugi.bio/variant/arx-p-ser213

## Summary

**ARX p.Ser213= (c.639C>T)** is classified **Likely benign** in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-13). Very rare (popmax 0.000115%, nfe); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

**At a glance:** Likely benign · review: Single submitter · rsID rs2048710797 · 1 submitter · 2 linked conditions · very rare (popmax 0.000115%, nfe)

## 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 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.Ser213= |
| Coding change (HGVS c.) | c.639C>T |
| MANE Select transcript | [NM_139058](https://www.ncbi.nlm.nih.gov/nuccore/NM_139058) |
| dbSNP | [rs2048710797](https://www.ncbi.nlm.nih.gov/snp/rs2048710797/) |
| Variant type | single nucleotide variant |
| Location | chrX:25013356-25013356 (GRCh38) |
| ClinVar | [VCV1099552](https://www.ncbi.nlm.nih.gov/clinvar/variation/1099552/) |

**All HGVS expressions:** `NC_000023.10:g.25031473G>A`, `NC_000023.11:g.25013356G>A`, `NG_008281.1:g.7593C>T`, `NM_139058.3:c.639C>T`

## 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 -0.082, GERP -1.98, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.168**. 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 **0.000115%** (nfe) · 1/867,760 in the highest group · 1/110,135 alleles overall — very rare (popmax 0.000115%, nfe).

*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}

Residue **213** lies in the 'disordered' region.

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. p.Ser213= falls in the disordered region.


### 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 2023-05-13.

**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 | 2023-05-13 |

## 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, Mental retardation, X-linked 52.

## Similar variants {#similar}

Related ARX variant pages (same residue, condition, or type): [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), [ARX p.Glu294Ter](/variant/arx-p-glu294ter), [ARX p.Pro353Leu](/variant/arx-p-pro353leu).

### 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 1099552). 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.*