Is MECP2 p.Ser408Phe (c.1223C>T) pathogenic?

MECP2 p.Ser408Phe (c.1223C>T) is classified Likely benign in MECP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1913); Very rare (popmax 0.00437%, nfe); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Ser408Phe (c.1223C>T)?

MECP2 p.Ser408Phe (c.1223C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ser408Phe (c.1223C>T) in the general population?

MECP2 p.Ser408Phe (c.1223C>T) is very rare (popmax 0.00437%, nfe) (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

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

What do computational predictors say about MECP2 p.Ser408Phe (c.1223C>T)?

AlphaMissense predicts likely benign (score 0.1913) — an in-silico prediction, not a clinical call.

MECP2 p.Ser408Phe

c.1223C>T · rs782125862 · VCV748765

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00437%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.1913	likely benign
REVEL	0.402	indeterminate
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	23.7	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 S396F vs ClinVar S408F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00437% European (non-Finnish) · 39/891,768 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00334% 40/1,198,345 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00437%	22,866
Remaining individualsnot grpmax-eligible	0.00211%	47,360

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.Ser408Phe
Coding: c.1223C>T
MANE Select: NM_001110792
dbSNP: rs782125862
Type: single nucleotide variant
Location: chrX:154030641 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 396 UniProt numbering: 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.Ser408= Benign ★★★ 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
MECP2 p.Arg179Trp 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-ser408phe (accessed [today's date]).

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