MECP2 p.Ser82Pro
c.244T>C · rs1557137884 · VCV560190
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Uncertain Significance for Rett syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting BS2
Curation rationale (ClinGen, verbatim)
The p.Ser70Pro variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (Labcorp (formerly Invitae)- internal database, GeneDx-internal database) and has not been previously published as associated with disease (BS2). The p.Ser70Pro variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Ser70Pro variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, PM2_Supporting). (MECP2 Specifications v.5.0; curation approved on 01/28/2026).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1214 | likely benign |
|---|---|---|
| REVEL | 0.536 | indeterminate |
| SaProt | LLR -6.19 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 2.3 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 1.06 | unconstrained · MANE · 65 kb · p 0.54 · regional, not allelic |
| Overall | ||
| CADD | 16.2 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S70P vs ClinVar S82P) — verify the residue.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- MECP2
- Protein
- p.Ser82Pro
- Coding
- c.244T>C
- MANE Select
- NM_001110792
- dbSNP
- rs1557137884
- Type
- single nucleotide variant
- Location
- chrX:154032376 (GRCh38)
- Structure
- AlphaFold pLDDT 57.25 · 11 PDB
- Residue 70 UniProt numbering
- 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.Ser82= Benign/Likely benign ★★ same residue
- MECP2 p.Ser82Cys Uncertain significance ★ ⚠ 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-ser82pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown