# NM_001110792.2(MECP2):c.942C>G (p.Pro314=)

https://sugi.bio/variant/mecp2-p-pro314

## Summary

**MECP2 p.Pro314= (c.942C>G)** is classified **Benign/Likely benign** in MECP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-24). Ultra-rare (popmax 0.0435%, afr); Associated with severe neonatal-onset encephalopathy with microcephaly.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs61751438 · 5 submitters · 2 linked conditions · ultra-rare (popmax 0.0435%, afr)

## For patients & families {#patients}

This is a change in the MECP2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to severe neonatal-onset encephalopathy with microcephaly.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | MECP2 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of MECP2-related severe neonatal encephalopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Encephalopathy — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Apnea — Very frequent (99-80%)
- Severe global developmental delay — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Growth delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017103/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.Pro314= |
| Coding change (HGVS c.) | c.942C>G |
| MANE Select transcript | [NM_001110792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792) |
| dbSNP | [rs61751438](https://www.ncbi.nlm.nih.gov/snp/rs61751438/) |
| Variant type | single nucleotide variant |
| Location | chrX:154030922-154030922 (GRCh38) |
| ClinVar | [VCV143739](https://www.ncbi.nlm.nih.gov/clinvar/variation/143739/) |

**All HGVS expressions:** `AJ132917.1:c.906C>G`, `LRG_764:g.111182C>G`, `LRG_764t1:c.942C>G`, `LRG_764t2:c.906C>G`, `NC_000023.10:g.153296373G>C`, `NC_000023.11:g.154030922G>C`, `NG_007107.3:g.111182C>G`, `NM_001110792.2:c.942C>G`, `NM_001316337.2:c.627C>G`, `NM_001369391.2:c.627C>G`, `NM_001369392.2:c.627C>G`, `NM_001369393.2:c.627C>G`, `NM_001369394.2:c.627C>G`, `NM_001386137.1:c.237C>G`, `NM_001386138.1:c.237C>G`, `NM_001386139.1:c.237C>G`, `NM_004992.4:c.906C>G`

## 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 1.02, GERP -1.03, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 6.209**. 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 **0.0435%** (afr) · FAF95 0.0303% · FAF99 0.0258% · 25/57,433 in the highest group · 28/1,210,687 alleles overall — ultra-rare (popmax 0.0435%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0435% | 2,297 |
| Remaining individuals (not grpmax-eligible) | 0.0042% | 23,813 |
| European (non-Finnish) | 0.000112% | 895,263 |

*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 **314** lies in a UniProt-annotated variant site (in rtt).

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-24.

**Submitter consensus:** conflicting (3 Likely benign, 2 Benign).

**Submission history:** 5 submissions (2007–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| RettBASE | Benign | no assertion criteria provided | curation | 2007-11-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-23 |
| Centre for Population Genomics, CPG | Benign | criteria provided, single submitter | curation | 2024-03-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-06-03 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-24 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Severe neonatal-onset encephalopathy with microcephaly, not specified, MECP2-related disorder, Rett syndrome, MECP2-related disorders, MECP2-related condition, AllHighlyPenetrant, MECP2-Related Severe Neonatal Encephalopathy, Encephalopathy, neonatal severe, AUTISM, DEMENTIA, ATAXIA, AND LOSS OF PURPOSEFUL HAND USE.

## Same-residue context {#hotspot}

Residue **314** carries **7 other pathogenic ClinVar variants** — a recurrently-mutated position: [MECP2 p.Pro314Thr](/variant/mecp2-p-pro314thr), [MECP2 p.Pro314Ala](/variant/mecp2-p-pro314ala), [MECP2 p.Pro314Ser](/variant/mecp2-p-pro314ser), [MECP2 p.Pro314His](/variant/mecp2-p-pro314his), [MECP2 p.Pro314Arg](/variant/mecp2-p-pro314arg), [MECP2 p.Pro314Leu](/variant/mecp2-p-pro314leu), [MECP2 p.Pro314_Ala390delinsArgThrSerTer](/variant/mecp2-p-pro314-ala390delinsargthrserter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MECP2 variant pages (same residue, condition, or type): [MECP2 p.Pro314Leu](/variant/mecp2-p-pro314leu), [MECP2 p.Pro314Ala](/variant/mecp2-p-pro314ala), [MECP2 p.Pro314Arg](/variant/mecp2-p-pro314arg), [MECP2 p.Pro314His](/variant/mecp2-p-pro314his), [MECP2 p.Pro314Ser](/variant/mecp2-p-pro314ser), [MECP2 p.Pro314Thr](/variant/mecp2-p-pro314thr), [MECP2 c.414-3C>G](/variant/mecp2-c-414-minus-3c-g), [MECP2 c.62+1G>A](/variant/mecp2-c-62-plus-1g-a).

### 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 143739). 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.*