Is MECP2 p.Ala299Pro (c.895G>C) pathogenic?

MECP2 p.Ala299Pro (c.895G>C) is classified Likely benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2021-10-28). AlphaMissense: likely benign (0.296); Very rare (popmax 0.00112%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Ala299Pro (c.895G>C)?

MECP2 p.Ala299Pro (c.895G>C) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ala299Pro (c.895G>C) in the general population?

MECP2 p.Ala299Pro (c.895G>C) is very rare (popmax 0.00112%, nfe) (gnomAD).

How is Rett syndrome inherited?

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

What do computational predictors say about MECP2 p.Ala299Pro (c.895G>C)?

AlphaMissense predicts likely benign (score 0.296) — an in-silico prediction, not a clinical call.

MECP2 p.Ala299Pro

c.895G>C · rs61750257 · VCV143716

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for Rett syndrome. Applied ACMG criteria (verbatim):

BS2 BP5 BP2

Curation rationale (ClinGen, verbatim)

The p.Ala287Pro variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx, internal database - Baylor) (BS2). The p.Ala287Pro variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (internal database - GeneDx) (BP2). The p.Ala287Pro variant is found in a patient with an alternate molecular basis of disease (internal database - Baylor) (BP5). The p.Ala287Pro variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.001638% (no criteria met). In summary, the p.Ala287Pro variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP2, BP5).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.296	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -8.41	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 2.6	GERP 0.3, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	21.6	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 A287P vs ClinVar A299P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00112% European (non-Finnish) · 10/895,574 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000412%

Overall 0.000907% 11/1,212,126 alleles · very rare exomes 11/1,098,220 · genomes 0/113,906 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,656
European (non-Finnish)grpmax	0.00112%	89,558

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala299Pro
Coding: c.895G>C
MANE Select: NM_001110792
dbSNP: rs61750257
Type: single nucleotide variant
Location: chrX:154030969 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 287 UniProt numbering: the 'interaction with ncor2' region; a UniProt-annotated variant site (in rtt); the 'interaction with tbl1xr1' region; a UniProt-annotated variant site (in)

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe neonatal-onset encephalopathy with microcephaly

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MECP2 p.Ala299Asp Uncertain significance ★ ⚠ same residue
MECP2 p.Ala299Val Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Ala299= Likely benign ★ same residue
MECP2 p.Ala299fs Pathogenic ★ 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-ala299pro (accessed [today's date]).

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