# NM_001110792.2(MECP2):c.1458T>C (p.Pro486=)

https://sugi.bio/variant/mecp2-p-pro486

## Summary

**MECP2 p.Pro486= (c.1458T>C)** is classified **Likely benign** in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-04-18). Very rare (popmax 0.000894%, nfe); Associated with Rett syndrome.

**At a glance:** Likely benign · review: Expert panel · rsID rs1557134910 · 5 submitters · 2 linked conditions · very rare (popmax 0.000894%, nfe)

## For patients & families {#patients}

This is a change in the MECP2 gene that is classified as likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Rett syndrome.

*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) | X-linked dominant |
| Age of onset (of this condition) | Infancy |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 90 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MECP2 is a diagnostic-grade gene on 8 Genomics England panels |

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

- Progressive microcephaly — Very frequent (99-80%)
- Abnormal repetitive mannerisms — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Absent speech — Very frequent (99-80%)
- Developmental regression — Very frequent (99-80%)
- Abnormal pattern of respiration — Very frequent (99-80%)
- Progressive language deterioration — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005696/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MECP2](https://sugi.bio/atlas/gene/MECP2/) |
| Protein change (HGVS p.) | p.Pro486= |
| Coding change (HGVS c.) | c.1458T>C |
| MANE Select transcript | [NM_001110792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792) |
| dbSNP | [rs1557134910](https://www.ncbi.nlm.nih.gov/snp/rs1557134910/) |
| Variant type | single nucleotide variant |
| Location | chrX:154030406-154030406 (GRCh38) |
| ClinVar | [VCV516510](https://www.ncbi.nlm.nih.gov/clinvar/variation/516510/) |

**All HGVS expressions:** `LRG_764:g.111698T>C`, `LRG_764t1:c.1458T>C`, `LRG_764t2:c.1422T>C`, `NC_000023.10:g.153295857A>G`, `NC_000023.11:g.154030406A>G`, `NG_007107.3:g.111698T>C`, `NM_001110792.2:c.1458T>C`, `NM_001316337.2:c.1143T>C`, `NM_001369391.2:c.1143T>C`, `NM_001369392.2:c.1143T>C`, `NM_001369393.2:c.1143T>C`, `NM_001369394.2:c.1143T>C`, `NM_001386137.1:c.753T>C`, `NM_001386138.1:c.753T>C`, `NM_001386139.1:c.753T>C`, `NM_004992.4:c.1422T>C`

## 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 5.114, GERP 0.657, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.565**. 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 **0.000894%** (nfe) · FAF95 0.000384% · FAF99 0.000278% · 8/895,312 in the highest group · 8/1,211,236 alleles overall — very rare (popmax 0.000894%, 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}

**MECP2** 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):

- **Rett syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **486** lies in a UniProt-annotated variant site (in rtt); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 57.25, 9% of residues very-high.

**11 experimental structure(s)** (PDB): [1QK9](https://www.rcsb.org/structure/1QK9), [3C2I](https://www.rcsb.org/structure/3C2I), [5BT2](https://www.rcsb.org/structure/5BT2), [6C1Y](https://www.rcsb.org/structure/6C1Y), [6OGJ](https://www.rcsb.org/structure/6OGJ), [6OGK](https://www.rcsb.org/structure/6OGK) — incl. mutant structure 8AJR.

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

*Describes the biological roles of MECP2 (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:** MECP2's established molecular role includes nucleic acid binding. p.Pro486= falls in the disordered region. In Reactome, MECP2 is annotated in disease pathway(s) including **Loss of MECP2 binding ability to 5hmC-DNA**, **Loss of MECP2 binding ability to 5mC-DNA**.

**Disease mechanism (Reactome):** MECP2 loss or alteration is curated in [Loss of MECP2 binding ability to 5hmC-DNA](https://reactome.org/content/detail/R-HSA-9022534), [Loss of MECP2 binding ability to 5mC-DNA](https://reactome.org/content/detail/R-HSA-9022538), [Loss of MECP2 binding ability to the NCoR/SMRT complex](https://reactome.org/content/detail/R-HSA-9022537).

### Pathways affected {#pathways}

MECP2 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Loss of MECP2 binding ability to 5hmC-DNA](https://reactome.org/content/detail/R-HSA-9022534) | other |
| ⚕ [Loss of MECP2 binding ability to 5mC-DNA](https://reactome.org/content/detail/R-HSA-9022538) | other |
| ⚕ [Loss of MECP2 binding ability to the NCoR/SMRT complex](https://reactome.org/content/detail/R-HSA-9022537) | other |
| ⚕ [Loss of phosphorylation of MECP2 at T308](https://reactome.org/content/detail/R-HSA-9022535) | other |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | other |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | other |
| [MECP2 regulates transcription factors](https://reactome.org/content/detail/R-HSA-9022707) | other |
| [MECP2 regulates transcription of genes involved in GABA signaling](https://reactome.org/content/detail/R-HSA-9022927) | other |
| [MECP2 regulates transcription of neuronal ligands](https://reactome.org/content/detail/R-HSA-9022702) | other |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | other |
| [Transcriptional Regulation by MECP2](https://reactome.org/content/detail/R-HSA-8986944) | other |

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

**Molecular function:** nucleic acid binding, transcription corepressor activity, RNA binding, double-stranded methylated DNA binding, molecular adaptor activity, molecular condensate scaffold activity.

**Biological process:** negative regulation of gene expression, negative regulation of angiogenesis, negative regulation of blood vessel endothelial cell migration, negative regulation of gene expression via chromosomal CpG island methylation, negative regulation of DNA-templated transcription, genomic imprinting.

## Clinical significance {#significance}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-04-18.

**Submitter consensus:** conflicting (2 Likely benign, 2 Uncertain significance, 1 Likely Benign).

**Submission history:** 5 submissions (2018–2024); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Rett and Angelman-like Disorders VCEP (Rett syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS2_Supporting`, `BP5`, `BP4`.
*Considered but not met:* `PM2`, `BS1`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The highest population minor allele frequency of the p.Pro474= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008935 in European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro474= variant is observed in at least 1 unaffected individual (GeneDx internal database) (BS2_supporting). The p.Pro474= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Splice prediction analysis does not suggest an impact to splicing (BP4). In summary, the p.Pro474= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2_supporting, BP5, BP4).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50022 · approved 2024-04-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/4b9145aa-2ae7-4e22-93bb-533ed5e9a32d).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-29 |
| Athena Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-05 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-16 |
| ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Likely Benign | reviewed by expert panel | curation | 2024-04-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-16 |

## Associated conditions {#conditions}

[Rett syndrome](https://sugi.bio/atlas/disease/rett-syndrome/), [severe neonatal-onset encephalopathy with microcephaly](https://sugi.bio/atlas/disease/severe-neonatal-onset-encephalopathy-with-microcephaly/).

**Reported phenotype names (ClinVar):** Rett syndrome, not specified, not provided, Severe neonatal-onset encephalopathy with microcephaly, none provided, Encephalopathy, neonatal severe, MECP2-Related Severe Neonatal Encephalopathy, AllHighlyPenetrant, Rett's disorder, AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE.

## Similar variants {#similar}

Related MECP2 variant pages (same residue, condition, or type): [MECP2 c.414-3C>G](/variant/mecp2-c-414-minus-3c-g), [MECP2 c.62+1G>A](/variant/mecp2-c-62-plus-1g-a), [MECP2 c.62+2T>G](/variant/mecp2-c-62-plus-2t-g), [MECP2 p.Ala143Asp](/variant/mecp2-p-ala143asp), [MECP2 p.Ala291Val](/variant/mecp2-p-ala291val), [MECP2 p.Arg127His](/variant/mecp2-p-arg127his), [MECP2 p.Arg145Cys](/variant/mecp2-p-arg145cys), [MECP2 p.Arg145His](/variant/mecp2-p-arg145his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 516510). 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.*