# NM_001110792.2(MECP2):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/mecp2-p-arg306gln

## Summary

**MECP2 p.Arg306Gln (c.917G>A)** is classified **Likely benign** in MECP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0936); Very rare (popmax 0.00176%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs61751366 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00176%, sas)

## For patients & families {#patients}

This is a change in the MECP2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 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.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_001110792](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792) |
| dbSNP | [rs61751366](https://www.ncbi.nlm.nih.gov/snp/rs61751366/) |
| Variant type | single nucleotide variant |
| Location | chrX:154030947-154030947 (GRCh38) |
| ClinVar | [VCV1131428](https://www.ncbi.nlm.nih.gov/clinvar/variation/1131428/) |

**All HGVS expressions:** `LRG_764:g.111157G>A`, `LRG_764t1:c.917G>A`, `LRG_764t2:c.881G>A`, `NC_000023.10:g.153296398C>T`, `NC_000023.11:g.154030947C>T`, `NG_007107.3:g.111157G>A`, `NM_001110792.2:c.917G>A`, `NM_001316337.2:c.602G>A`, `NM_001369391.2:c.602G>A`, `NM_001369392.2:c.602G>A`, `NM_001369393.2:c.602G>A`, `NM_001369394.2:c.602G>A`, `NM_001386137.1:c.212G>A`, `NM_001386138.1:c.212G>A`, `NM_001386139.1:c.212G>A`, `NM_004992.4:c.881G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0936)
- REVEL 0.396 (indeterminate)
- SaProt LLR -5.67 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 5.811, GERP 1.4, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R294Q** vs ClinVar **R306Q**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 21.8**. 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.*
- Regional missense constraint: **o/e 1.55** across the covering region of the MANE Select transcript (154,030,370–154,031,422), spanning 1,052 bp. Chi-square p 2.6e-22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.23 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00176%** (sas) · FAF95 0.000659% · FAF99 0.000482% · 1/56,887 in the highest group · 14/1,210,532 alleles overall — very rare (popmax 0.00176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0042% | 23,804 |
| South Asian (grpmax) | 0.00176% | 56,887 |
| European (non-Finnish) | 0.00123% | 81,389 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **294** lies in the 'interaction with ncor2' region; a UniProt-annotated variant site (in rtt); the 'interaction with tbl1xr1' 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.Arg306Gln falls in the interaction with ncor2 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-06.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-06 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-10-01 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-09-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Severe neonatal-onset encephalopathy with microcephaly, MECP2-related disorder, not provided, MECP2-related condition, MECP2-related disorders, none provided, Encephalopathy, neonatal severe, MECP2-Related Severe Neonatal Encephalopathy.

## Same-residue context {#hotspot}

Residue **306** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MECP2 p.Arg306Ter](/variant/mecp2-p-arg306ter), [MECP2 p.Arg306fs](/variant/mecp2-p-arg306fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MECP2 variant pages (same residue, condition, or type): [MECP2 p.Arg306Ter](/variant/mecp2-p-arg306ter), [MECP2 p.Arg306=](/variant/mecp2-p-arg306), [MECP2 p.Arg306Gly](/variant/mecp2-p-arg306gly), [MECP2 p.Arg306Pro](/variant/mecp2-p-arg306pro), [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 p.Ala291Val](/variant/mecp2-p-ala291val), [MECP2 p.Arg127His](/variant/mecp2-p-arg127his).

### 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 1131428). 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.*