Is MECP2 p.Arg267Pro (c.800G>C) pathogenic?

MECP2 p.Arg267Pro (c.800G>C) is classified Pathogenic in MECP2 (ClinVar, Expert panel, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.9638); Absent from gnomAD v4.1; Associated with Rett syndrome.

What condition is associated with MECP2 p.Arg267Pro (c.800G>C)?

MECP2 p.Arg267Pro (c.800G>C) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Arg267Pro (c.800G>C) in the general population?

MECP2 p.Arg267Pro (c.800G>C) is absent from gnomAD v4.1 (gnomAD).

How is Rett syndrome inherited?

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

What do computational predictors say about MECP2 p.Arg267Pro (c.800G>C)?

AlphaMissense predicts likely pathogenic (score 0.9638) — an in-silico prediction, not a clinical call.

MECP2 p.Arg267Pro

c.800G>C · rs2065944203 · VCV2229884

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9638 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Pathogenic for Rett syndrome. Applied ACMG criteria (verbatim):

PM6 PS2_VeryStrong PM2_Supporting PS4_Moderate

Curation rationale (ClinGen, verbatim)

The p.Arg255Pro variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 individuals with features of Rett syndrome (Ambry Genetics- internal database, GeneDx- internal database) (PS2_Very strong). The p.Arg255Pro variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with features of Rett syndrome (GeneDx- internal database) (PM6). The p.Arg255Pro variant has been observed in 3 individuals with affected with a neurodevelopmental phenotype consistent with MECP2-related conditions (Labcorp Genetics (formerly Invitae)- internal database; Ambry Genetics- internal database) (PS4_moderate). The p.Arg255Pro variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Arg255Pro variant in MECP2 is classified as Pathogenic based on the ACMG/AMP criteria (PS2_very-strong, PM6, PS4_moderate, 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	0.9638	likely pathogenic ✓ concordant with ClinVar
REVEL	0.617	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 0.22, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R255P vs ClinVar R267P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

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.Arg267Pro
Coding: c.800G>C
MANE Select: NM_001110792
dbSNP: rs2065944203
Type: single nucleotide variant
Location: chrX:154031064 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 255 UniProt numbering: 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

Also 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.Arg267Ter Pathogenic/Likely pathogenic ★★ same residue
MECP2 p.Arg267= Likely benign ★ same residue
MECP2 p.Arg267fs Pathogenic ★ same residue
MECP2 p.Arg267Gly Pathogenic/Likely 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

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-arg267pro (accessed [today's date]).

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