Is MECP2 p.Ala451= (c.1353G>A) pathogenic?

MECP2 p.Ala451= (c.1353G>A) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-18). Ultra-rare (popmax 0.023%, mid); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Ala451= (c.1353G>A)?

MECP2 p.Ala451= (c.1353G>A) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ala451= (c.1353G>A) in the general population?

MECP2 p.Ala451= (c.1353G>A) is ultra-rare (popmax 0.023%, mid) (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.Ala451=

c.1353G>A · rs146632223 · VCV506488

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.1	GERP -1.9
Overall
CADD	2.023	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,354 alleles

Filtering AF 0.00695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00635%

Overall 0.00727% 88/1,209,676 alleles · ultra-rare exomes 83/1,098,182 · genomes 5/111,494 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,354
South Asian	0.00881%	11,352
European (non-Finnish)	0.00849%	11,778
East Asian	0.00593%	16,870
Remaining individualsnot grpmax-eligible	0.0042%	23,810
Admixed American	0.00219%	45,756
African / African-American	0.00175%	57,094

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.Ala451=
Coding: c.1353G>A
MANE Select: NM_001110792
dbSNP: rs146632223
Type: single nucleotide variant
Location: chrX:154030511 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 451: 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.Ala451Ser Benign ★★★ same residue
MECP2 p.Ala451Thr Benign/Likely benign ★★ same residue
MECP2 p.Ala451Val Benign/Likely benign ★★ same residue
MECP2 p.Ala451fs Pathogenic ★ 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

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-ala451 (accessed [today's date]).

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