Is MECP2 p.Ser423= (c.1269C>T) pathogenic?

MECP2 p.Ser423= (c.1269C>T) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-03). Common (popmax 23.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with History of neurodevelopmental disorder.

What condition is associated with MECP2 p.Ser423= (c.1269C>T)?

MECP2 p.Ser423= (c.1269C>T) is associated with History of neurodevelopmental disorder, severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

MECP2 p.Ser423=

Q: How common is MECP2 p.Ser423= (c.1269C>T) in the general population?

MECP2 p.Ser423= (c.1269C>T) is common (popmax 23.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1269C>T · rs3027928 · VCV95189

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 23.1%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

History of neurodevelopmental disorder

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 -0.24	GERP -2.8
Overall
CADD	2.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.1% Admixed American · 10,483/45,346 alleles

Filtering AF 22.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.6%

Overall 0.975% 11,744/1,204,764 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	23.1%	4
Remaining individualsnot grpmax-eligible	1.24%	80
East Asian	0.867%	115
African / African-American	0.4%	250
European (non-Finnish)	0.0163%	6,125
Finnishnot grpmax-eligible	0.00681%	14,687
South Asian	0.0053%	18,861

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.Ser423=
Coding: c.1269C>T
MANE Select: NM_001110792
dbSNP: rs3027928
Type: single nucleotide variant
Location: chrX:154030595 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 423: a modified residue (phosphoserine); 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

History of neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe neonatal-onset encephalopathy with microcephaly Rett syndrome

Similar variants

MECP2 p.Ser423Thr Uncertain significance ★ ⚠ same residue
MECP2 p.Ser423del Likely benign ★★★ same residue
MECP2 p.Ser423fs Likely pathogenic ★ same residue
MECP2 p.Ser423_Cys425del Uncertain significance ★ same residue
MECP2 p.Ser423Asn 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

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-ser423 (accessed [today's date]).

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