Is MECP2 p.Pro242= (c.726A>C) pathogenic?

MECP2 p.Pro242= (c.726A>C) is classified Likely benign in MECP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). Very rare (popmax 0.00751%, nfe); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro242= (c.726A>C)?

MECP2 p.Pro242= (c.726A>C) is associated with severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Pro242= (c.726A>C) in the general population?

MECP2 p.Pro242= (c.726A>C) is very rare (popmax 0.00751%, 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.

MECP2 p.Pro242=

c.726A>C · rs61749740 · VCV143660

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00751%, nfe)

Conditions

severe neonatal-onset encephalopathy with microcephaly

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 -11	GERP -2.6
Overall
CADD	0.296	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00751% European (non-Finnish) · 67/892,447 alleles

Filtering AF 0.006% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00551%

Overall 0.0058% 70/1,205,870 alleles · very rare exomes 67/1,095,886 · genomes 3/109,984 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00751%	13,320
Remaining individualsnot grpmax-eligible	0.00631%	15,836

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.Pro242=
Coding: c.726A>C
MANE Select: NM_001110792
dbSNP: rs61749740
Type: single nucleotide variant
Location: chrX:154031138 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 242: 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

Also linked: Rett syndrome

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro242Thr Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro242Ala Uncertain significance ★ ⚠ same residue
MECP2 p.Pro242fs Pathogenic/Likely pathogenic ★★ same residue
MECP2 p.Pro242Ser Likely benign ★ 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-pro242 (accessed [today's date]).

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