Is MECP2 p.Ala91= (c.273C>G) pathogenic?

MECP2 p.Ala91= (c.273C>G) is classified Likely benign in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-09). Very rare (popmax 0.00347%, afr); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Ala91= (c.273C>G)?

MECP2 p.Ala91= (c.273C>G) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ala91= (c.273C>G) in the general population?

MECP2 p.Ala91= (c.273C>G) is very rare (popmax 0.00347%, afr) (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.Ala91=

c.273C>G · rs374659909 · VCV2428141

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00347%, afr)

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 0.47	GERP -0.5, phastCons 0.98
Overall
CADD	8.592	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% African / African-American · 2/57,641 alleles

Filtering AF 0.000576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000215%

Overall 0.000495% 6/1,211,025 alleles · very rare exomes 5/1,097,789 · genomes 1/113,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00347%	28,821
East Asian	0.00296%	33,789
Remaining individualsnot grpmax-eligible	0.0021%	47,599
South Asian	0.00176%	56,933
European (non-Finnish)	0.000112%	895,151

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.Ala91=
Coding: c.273C>G
MANE Select: NM_001110792
dbSNP: rs374659909
Type: single nucleotide variant
Location: chrX:154032347 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 91: the mbd domain; a turn; 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.Ala91Ser 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
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-ala91 (accessed [today's date]).

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