Is MECP2 p.Pro403Ala (c.1207C>G) pathogenic?

MECP2 p.Pro403Ala (c.1207C>G) is classified Likely benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-08-30). AlphaMissense: likely benign (0.0607); Very rare (popmax 0.000337%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro403Ala (c.1207C>G)?

MECP2 p.Pro403Ala (c.1207C>G) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro403Ala (c.1207C>G) in the general population?

MECP2 p.Pro403Ala (c.1207C>G) is very rare (popmax 0.000337%, 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.Pro403Ala (c.1207C>G)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

MECP2 p.Pro403Ala

c.1207C>G · rs781794820 · VCV426939

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000337%, 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

Curation rationale (ClinGen, verbatim)

The p.Pro391Ala variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Invitae and GeneDx) (BS2). The p.Pro391Ala variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro391Ala variant in MECP2 (NM_004992.4) is classified as likely benign for Rett syndrome based on the ACMG/AMP criteria (BS2). (MECP2 specification v.3.0.0, curation approved on 8/30/2024)

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

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -7.74	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 6.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	14.98	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 P391A vs ClinVar P403A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000337% European (non-Finnish) · 3/889,267 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000251% 3/1,195,797 alleles · very rare exomes 3/1,088,672 · genomes 0/107,125 · joint denominator

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.Pro403Ala
Coding: c.1207C>G
MANE Select: NM_001110792
dbSNP: rs781794820
Type: single nucleotide variant
Location: chrX:154030657 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 391 UniProt numbering: 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

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.Pro403Thr Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro403= Likely benign ★ same residue
MECP2 p.Pro403_Glu404insTer Pathogenic/Likely pathogenic ★★ same residue
MECP2 p.Pro403fs Pathogenic ★ same residue
MECP2 p.Pro403del Conflicting classifications of pathogenicity ★ 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-pro403ala (accessed [today's date]).

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