# NM_001110792.2(MECP2):c.203_204del (p.Pro68fs)

https://sugi.bio/variant/mecp2-p-pro68fs

## Summary

**MECP2 p.Pro68fs (c.203_204del)** is classified **Pathogenic** in MECP2 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-01-11). No gnomAD frequency available for this variant; Associated with Rett syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs267608434 · 3 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MECP2 gene that is reported as disease-causing, but on limited review, submitted by 3 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.Pro68fs |
| Coding change (HGVS c.) | c.203_204del |
| MANE Select transcript | [NM_001110792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792) |
| dbSNP | [rs267608434](https://www.ncbi.nlm.nih.gov/snp/rs267608434/) |
| Variant type | Deletion |
| Location | chrX:154032416-154032417 (GRCh38) |
| ClinVar | [VCV11818](https://www.ncbi.nlm.nih.gov/clinvar/variation/11818/) |

**All HGVS expressions:** `AJ132917.1:c.167_168delCC`, `LRG_764:g.109687_109688del`, `LRG_764t1:c.203_204del`, `LRG_764t2:c.167_168del`, `NC_000023.10:g.153297868_153297869del`, `NC_000023.11:g.154032417_154032418del`, `NG_007107.3:g.109687_109688del`, `NM_001110792.2:c.203_204del`, `NM_001316337.2:c.-113_-112del`, `NM_001369391.2:c.-113_-112del`, `NM_001369392.2:c.-113_-112del`, `NM_001369393.2:c.-113_-112del`, `NM_001369394.2:c.-113_-112del`, `NM_001386137.1:c.-394_-393del`, `NM_001386138.1:c.-394_-393del`, `NM_001386139.1:c.-394_-393del`, `NM_004992.3:c.167_168delCC`, `NM_004992.4:c.167_168del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.925, GERP 1.37, phastCons 0.999 — highly conserved position (PP3-type support)
- 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 2 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- 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}

**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 **68** lies in 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.Pro68fs 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-11.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2000–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2000-09-02 |
| RettBASE | Pathogenic | no assertion criteria provided | curation | 2002-04-10 |
| Centre for Population Genomics, CPG | Pathogenic | criteria provided, single submitter | curation | 2024-01-11 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related MECP2 variant pages (same residue, condition, or type): [MECP2 p.Pro68=](/variant/mecp2-p-pro68), [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).

### 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 11818). 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.*