Is MECP2 p.Ala299fs (c.891_895delinsAAAAAAAAGACT) pathogenic?

MECP2 p.Ala299fs (c.891895delinsAAAAAAAAGACT) is classified Pathogenic in MECP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-01). No gnomAD frequency available for this variant; Associated with Rett syndrome.

What condition is associated with MECP2 p.Ala299fs (c.891_895delinsAAAAAAAAGACT)?

MECP2 p.Ala299fs (c.891_895delinsAAAAAAAAGACT) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Ala299fs (c.891_895delinsAAAAAAAAGACT) in the general population?

MECP2 p.Ala299fs (c.891_895delinsAAAAAAAAGACT) is no gnomAD frequency available for this variant (gnomAD).

How is Rett syndrome inherited?

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

MECP2 p.Ala299fs

c.891_895delinsAAAAAAAAGACT · rs786205030 · VCV189729

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 2.6	GERP 0.3, 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.Ala299fs
Coding: c.891_895delinsAAAAAAAAGACT
MANE Select: NM_001110792
dbSNP: rs786205030
Type: Indel
Location: chrX:154030969 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 299: the 'interaction with ncor2' region; a UniProt-annotated variant site (in rtt); the 'interaction with tbl1xr1' 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.Ala299Pro Likely benign ★★★ same residue
MECP2 p.His384_Ser385delinsProGln Likely benign ★★★ same condition
MECP2 p.Pro400Ter Pathogenic ★★ same condition
MECP2 p.Pro401_Pro417delinsTer Pathogenic/Likely pathogenic ★★ same condition
MECP2 c.1276_*113del299ins3 Pathogenic ★ same condition
MECP2 c.27-4722_*112delinsCACTTTGTG Pathogenic ★ same condition
MECP2 c.27-5774_902delinsGTGCCCGGACTGATGTCA Pathogenic ★ same condition
MECP2 c.27-6026_1190delinsGT 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-ala299fs (accessed [today's date]).

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