Is MECP2 p.Arg145Pro (c.434G>C) pathogenic?

MECP2 p.Arg145Pro (c.434G>C) is classified Pathogenic/Likely pathogenic in MECP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with Rett syndrome.

What condition is associated with MECP2 p.Arg145Pro (c.434G>C)?

MECP2 p.Arg145Pro (c.434G>C) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Arg145Pro (c.434G>C) in the general population?

MECP2 p.Arg145Pro (c.434G>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.Arg145Pro (c.434G>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

MECP2 p.Arg145Pro

c.434G>C · rs61748389 · VCV1679147

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rett syndrome

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 5% in MECP2
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -15.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 886 bp · p 9.6e-08 · regional, not allelic
Overall
CADD	27.2	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 R133P vs ClinVar R145P) — 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.Arg145Pro
Coding: c.434G>C
MANE Select: NM_001110792
dbSNP: rs61748389
Type: single nucleotide variant
Location: chrX:154031430 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 133 UniProt numbering: the mbd domain; a β-strand; a UniProt-annotated variant site (in rtt; impairs interaction with atrx and abolishes atrx recruitment to heterochromatin); a UniProt-annotated variant site (in rtt)

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 p.Arg145Cys Pathogenic ★★★ same residue
MECP2 p.Arg145His Pathogenic ★★★ same residue
MECP2 p.Arg145Leu Pathogenic ★★★ same residue
MECP2 p.Arg145Gly Likely pathogenic ★ same residue
MECP2 p.Arg145Ser Likely pathogenic ★★ same residue
MECP2 p.Arg145= Likely benign ★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A 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-arg145pro (accessed [today's date]).

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