MECP2 p.Ser408=
c.1224C>T · rs781816931 · VCV211453
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Benign for Rett syndrome. Applied ACMG criteria (verbatim):
BS2_Supporting BA1
Curation rationale (ClinGen, verbatim)
The allele frequency of the p.Ser396= variant in MECP2 (NM_004992.3) is 0.15% in European (Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ser396= variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Ser396= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.026 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -1.1 | GERP -3.1 |
| Overall | ||
| CADD | 0.846 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Finnishnot grpmax-eligible | 0.133% | 750 |
| European (non-Finnish)grpmax | 0.0272% | 3,673 |
| Admixed American | 0.0132% | 7,560 |
| Remaining individualsnot grpmax-eligible | 0.0105% | 9,482 |
| East Asian | 0.00595% | 16,805 |
| South Asian | 0.00354% | 28,225 |
| African / African-American | 0.0018% | 55,632 |
Finnish shows a higher raw frequency than the grpmax group above it. 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.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- MECP2
- Protein
- p.Ser408=
- Coding
- c.1224C>T
- MANE Select
- NM_001110792
- dbSNP
- rs781816931
- Type
- single nucleotide variant
- Location
- chrX:154030640 (GRCh38)
- Structure
- AlphaFold pLDDT 57.25 · 11 PDB
- Residue 408
- a UniProt-annotated variant site (in rtt); the 'disordered' region
Disease context
Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: severe neonatal-onset encephalopathy with microcephaly
For Rett syndrome (Orphanet):
- Inheritance
- X-linked dominant
- Onset
- Infancy
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- MECP2 p.Ser408Phe Likely benign ★★ same residue
- MECP2 p.Ser408fs Pathogenic ★ same residue
- MECP2 c.414-3C>G Pathogenic ★★★ same condition
- MECP2 c.62+1G>A Pathogenic ★★★ same condition
- MECP2 c.62+2T>G Pathogenic ★★★ same condition
- MECP2 p.Ala143Asp Pathogenic ★★★ same condition
- MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same condition
- MECP2 p.Arg127His Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mecp2-p-ser408 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown