Is MECP2 p.Pro396fs (c.1186_1228del) pathogenic?

MECP2 p.Pro396fs (c.11861228del) is classified Pathogenic in MECP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-26). Absent from gnomAD; Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro396fs (c.1186_1228del)?

MECP2 p.Pro396fs (c.1186_1228del) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Pro396fs (c.1186_1228del) in the general population?

MECP2 p.Pro396fs (c.1186_1228del) is absent from gnomAD (gnomAD).

How is Rett syndrome inherited?

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

MECP2 p.Pro396fs

c.1186_1228del · rs63749023 · VCV143349

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MECP2
Protein: p.Pro396fs
Coding: c.1186_1228del
MANE Select: NM_001110792
dbSNP: rs63749023
Type: Deletion
Location: chrX:154030636 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 396: a UniProt-annotated variant site (in rtt); 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.Pro396_Ter499delinsXaa Likely pathogenic ★ same residue
MECP2 p.Pro396_Ser407delinsArg Uncertain significance ★ same residue
MECP2 p.Pro396Leu Benign ★★★ same residue
MECP2 p.Pro396Ser Benign ★★★ same residue
MECP2 p.Pro396_Pro397insTer Pathogenic ★★ same residue
MECP2 p.Gly281fs Pathogenic ★★★ same condition
MECP2 p.Ile305_Ser362del Likely pathogenic ★★★ same condition
MECP2 p.Val392fs 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-pro396fs (accessed [today's date]).

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