Is MECP2 p.Pro486= (c.1458T>C) pathogenic?

MECP2 p.Pro486= (c.1458T>C) is classified Likely benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-04-18). Very rare (popmax 0.000894%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro486= (c.1458T>C)?

MECP2 p.Pro486= (c.1458T>C) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro486= (c.1458T>C) in the general population?

MECP2 p.Pro486= (c.1458T>C) is very rare (popmax 0.000894%, nfe) (gnomAD).

How is Rett syndrome inherited?

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

MECP2 p.Pro486=

c.1458T>C · rs1557134910 · VCV516510

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000894%, nfe)

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS2_Supporting BP5 BP4

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the p.Pro474= variant in MECP2 (NM_004992.3) in gnomAD v4.1 is 0.000008935 in European (Non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro474= variant is observed in at least 1 unaffected individual (GeneDx internal database) (BS2_supporting). The p.Pro474= variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Splice prediction analysis does not suggest an impact to splicing (BP4). In summary, the p.Pro474= variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2_supporting, BP5, BP4).

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.66, phastCons 1
Overall
CADD	9.565	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000894% European (non-Finnish) · 8/895,312 alleles

Filtering AF 0.000384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.00066% 8/1,211,236 alleles · very rare exomes 8/1,098,213 · genomes 0/113,023 · joint denominator

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.Pro486=
Coding: c.1458T>C
MANE Select: NM_001110792
dbSNP: rs1557134910
Type: single nucleotide variant
Location: chrX:154030406 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 486: 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

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 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
MECP2 p.Arg145His 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-pro486 (accessed [today's date]).

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