Is MECP2 p.Ser407= (c.1221C>T) pathogenic?

MECP2 p.Ser407= (c.1221C>T) is classified Benign in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). Ultra-rare (popmax 0.0852%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Ser407= (c.1221C>T)?

MECP2 p.Ser407= (c.1221C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ser407= (c.1221C>T) in the general population?

MECP2 p.Ser407= (c.1221C>T) is ultra-rare (popmax 0.0852%, sas) (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

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

MECP2 p.Ser407=

c.1221C>T · rs782775618 · VCV788163

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0852%, sas)

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.087	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.6, phastCons 1
Overall
CADD	9.807	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0852% South Asian · 48/56,368 alleles

Filtering AF 0.0659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0591%

Overall 0.00476% 57/1,196,852 alleles · ultra-rare exomes 56/1,091,726 · genomes 1/105,126 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0852%	1,174
Remaining individualsnot grpmax-eligible	0.0106%	9,470
African / African-American	0.00546%	18,302
European (non-Finnish)	0.000112%	891,528

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.Ser407=
Coding: c.1221C>T
MANE Select: NM_001110792
dbSNP: rs782775618
Type: single nucleotide variant
Location: chrX:154030643 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 407: 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

severe neonatal-onset encephalopathy with microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Ser407Gly Uncertain significance ★★ ⚠ same residue
MECP2 p.Ser407Cys Uncertain significance ★ ⚠ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A 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-ser407 (accessed [today's date]).

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