Is MECP2 p.Arg96fs (c.281_284dup) pathogenic?

MECP2 p.Arg96fs (c.281284dup) is classified Likely pathogenic in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-18). Associated with Rett syndrome.

What condition is associated with MECP2 p.Arg96fs (c.281_284dup)?

MECP2 p.Arg96fs (c.281_284dup) is associated with Rett syndrome (ClinVar).

How is Rett syndrome inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

MECP2 p.Arg96fs

c.281_284dup · VCV4293268

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Rett syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP 0.75, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MECP2
Protein: p.Arg96fs
Coding: c.281_284dup
MANE Select: NM_001110792
Type: Duplication
Location: chrX:154032335 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 96: the mbd domain; a β-strand; the 'disordered' region

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MECP2 p.Gly250fs Pathogenic/Likely pathogenic ★★ same condition
MECP2 p.Gly264fs Pathogenic/Likely pathogenic ★★ same condition
MECP2 p.Leu33fs Pathogenic/Likely pathogenic ★★ same condition
MECP2 p.Lys245fs Pathogenic ★★ same condition
MECP2 p.Thr111fs Pathogenic ★★ same condition
MECP2 p.Thr412fs Likely pathogenic ★★ same condition
MECP2 p.Arg96Trp Uncertain significance ★★ ⚠ same residue
MECP2 c.*98dup Benign/Likely benign ★★ 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-arg96fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown