MECP2 p.Arg179Pro
c.536G>C · rs2148663951 · VCV1489310
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Uncertain Significance for Rett syndrome. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting PM5
Curation rationale (ClinGen, verbatim)
The p.Arg167Pro variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). A pathogenic missense variant (p.Arg167Trp) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar) (PM5). The p.Arg167Pro variant has been observed in at least 2 individuals with Rett syndrome (PMID 34457282, internal database - Labcorp (formerly Invitae)) (PS4_Supporting). In summary, the p.Arg167Pro variant in MECP2 is classified as uncertain significance based on the ACMG/AMP criteria (PM2_Supporting, PM5, PS4_Supporting). (MECP2 Specifications v.5.0.0; curation approved on 8/27/2025)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9906 | likely pathogenic |
|---|---|---|
| REVEL | 0.63 | indeterminate |
| SaProt | LLR -10.73 | damaging |
| ⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 1.3, phastCons 1 |
| Regional constraint | o/e 1.55 | unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic |
| Overall | ||
| CADD | 26.8 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R167P vs ClinVar R179P) — 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.Arg179Pro
- Coding
- c.536G>C
- MANE Select
- NM_001110792
- dbSNP
- rs2148663951
- Type
- single nucleotide variant
- Location
- chrX:154031328 (GRCh38)
- Structure
- AlphaFold pLDDT 57.25 · 11 PDB
- Residue 179
- a β-strand; 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.Arg179Trp 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
- MECP2 p.Arg145Cys 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-arg179pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown