Is MECP2 p.Ser477Pro (c.1429T>C) pathogenic?

MECP2 p.Ser477Pro (c.1429T>C) is classified Uncertain significance in MECP2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.3887); Absent from gnomAD v4.1; Associated with Rett syndrome.

What condition is associated with MECP2 p.Ser477Pro (c.1429T>C)?

MECP2 p.Ser477Pro (c.1429T>C) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Ser477Pro (c.1429T>C) in the general population?

MECP2 p.Ser477Pro (c.1429T>C) is absent from gnomAD v4.1 (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.Ser477Pro (c.1429T>C)?

AlphaMissense predicts ambiguous (score 0.3887) — an in-silico prediction, not a clinical call.

MECP2 p.Ser477Pro

c.1429T>C · rs2522036958 · VCV2584881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3887 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Rett syndrome

Computational evidence

Protein change
AlphaMissense	0.3887	ambiguous
REVEL	0.404	indeterminate
SaProt	LLR -6.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	23.3	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 S465P vs ClinVar S477P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MECP2
Protein: p.Ser477Pro
Coding: c.1429T>C
MANE Select: NM_001110792
dbSNP: rs2522036958
Type: single nucleotide variant
Location: chrX:154030435 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 465 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

For Rett syndrome (Orphanet):

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

Similar variants

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
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

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-ser477pro (accessed [today's date]).

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