# NM_004992.3(MECP2):c.(?_1044)_(1442_?)del

https://sugi.bio/variant/mecp2-c-1044

## Summary

**MECP2 c.(?_1044** is classified **Pathogenic** in MECP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-12-05). Associated with Rett syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the MECP2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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/) |
| Coding change (HGVS c.) | c.(?_1044 |
| MANE Select transcript | [NM_001110792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792) (variant reported on NM_004992) |
| Variant type | Deletion |
| Location | chrX:None-None (GRCh38) |
| ClinVar | [VCV189639](https://www.ncbi.nlm.nih.gov/clinvar/variation/189639/) |

**All HGVS expressions:** `NC_000023.10:g.(?_153295837)_(153296235_?)del`, `NC_000023.11:g.(?_154030386)_(154030784_?)del`

## 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}


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. 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2013-12-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| RettBASE | Pathogenic | no assertion criteria provided | curation | 2013-12-05 |

## Associated conditions {#conditions}

[Rett syndrome](https://sugi.bio/atlas/disease/rett-syndrome/).

**Reported phenotype names (ClinVar):** Rett syndrome, AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE, Rett's disorder.

## Similar variants {#similar}

Related MECP2 variant pages (same residue, condition, or type): [MECP2 p.Gly281fs](/variant/mecp2-p-gly281fs), [MECP2 p.Ile305_Ser362del](/variant/mecp2-p-ile305-ser362del), [MECP2 p.Val392fs](/variant/mecp2-p-val392fs), [MECP2 p.His380fs](/variant/mecp2-p-his380fs), [MECP2 p.Leu394_Pro402del](/variant/mecp2-p-leu394-pro402del), [MECP2 p.Pro400_Pro479del](/variant/mecp2-p-pro400-pro479del), [MECP2 p.Glu406_Pro417del](/variant/mecp2-p-glu406-pro417del), [MECP2 p.Leu398_Pro399del](/variant/mecp2-p-leu398-pro399del).

### 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 189639). 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.*