Is MECP2 p.Ser387= (c.1161C>T) pathogenic?

MECP2 p.Ser387= (c.1161C>T) is classified Likely benign in MECP2 (ClinVar, Expert panel, 4 submitters; last evaluated 2023-10-13). Very rare (popmax 0.00297%, eas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Ser387= (c.1161C>T)?

MECP2 p.Ser387= (c.1161C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ser387= (c.1161C>T) in the general population?

MECP2 p.Ser387= (c.1161C>T) is very rare (popmax 0.00297%, eas) (gnomAD).

How is Rett syndrome inherited?

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

MECP2 p.Ser387=

c.1161C>T · rs782221170 · VCV500106

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00297%, eas)

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS2 BP4

Curation rationale (ClinGen, verbatim)

The c.1125C>T (p.Ser375=) variant in MECP2 (NM_004992.3) is present in 2 XY individuals in gnomAD (0.001%) (not sufficient to meet BS1 criteria). The p.Ser375= variant is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the p.Ser375= variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, 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 1.3	GERP -1.9, phastCons 1
Overall
CADD	6.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00297% East Asian · 1/33,660 alleles

Filtering AF 0.000474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000996% 12/1,204,678 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00297%	33,660
Admixed American	0.0022%	45,494
South Asian	0.00177%	56,487
European (non-Finnish)	0.00101%	99,216

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.Ser387=
Coding: c.1161C>T
MANE Select: NM_001110792
dbSNP: rs782221170
Type: single nucleotide variant
Location: chrX:154030703 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 387: 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 p.Ser387Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Ser387fs Likely pathogenic ★ same residue
MECP2 p.Ser387_Glu409del Uncertain significance ★ same residue
MECP2 p.Ser387_Gly440delinsTrp Uncertain significance ★ 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-ser387 (accessed [today's date]).

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