Is MECP2 p.Pro87= (c.261G>A) pathogenic?

MECP2 p.Pro87= (c.261G>A) is classified Likely benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2021-10-26). Very rare (popmax 0.00223%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro87= (c.261G>A)?

MECP2 p.Pro87= (c.261G>A) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro87= (c.261G>A) in the general population?

MECP2 p.Pro87= (c.261G>A) is very rare (popmax 0.00223%, nfe) (gnomAD).

How is Rett syndrome inherited?

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

MECP2 p.Pro87=

c.261G>A · rs61754442 · VCV143505

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, nfe)

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for Rett syndrome. Applied ACMG criteria (verbatim):

BS2 BP5

Curation rationale (ClinGen, verbatim)

The c.225G>A (p.Pro75=) variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The c.225G>A (p.Pro75=) variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). In summary, the c.225G>A (p.Pro75=) variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6.4	GERP -3.7
Overall
CADD	0.257	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% European (non-Finnish) · 20/895,271 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00173% 21/1,211,134 alleles · very rare exomes 18/1,097,886 · genomes 3/113,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00223%	44,764
South Asian	0.00176%	56,928

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MECP2
Protein: p.Pro87=
Coding: c.261G>A
MANE Select: NM_001110792
dbSNP: rs61754442
Type: single nucleotide variant
Location: chrX:154032359 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 87: 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.Pro87Leu Benign ★★★ 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-pro87 (accessed [today's date]).

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