Is MECP2 p.Pro113Arg (c.338C>G) pathogenic?

MECP2 p.Pro113Arg (c.338C>G) is classified Pathogenic in MECP2 (ClinVar, Expert panel, 6 submitters; last evaluated 2022-04-28). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro113Arg (c.338C>G)?

MECP2 p.Pro113Arg (c.338C>G) is associated with Rett syndrome, Angelman syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro113Arg (c.338C>G) in the general population?

MECP2 p.Pro113Arg (c.338C>G) 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.Pro113Arg (c.338C>G)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

MECP2 p.Pro113Arg

c.338C>G · rs61754453 · VCV143526

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Pathogenic for Rett syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PS4 PM5_Strong PP3

Curation rationale (ClinGen, verbatim)

The p.Pro101Arg variant in MECP2 (NM_004992.4) has been observed in 4 other individuals with Rett Syndrome (PMID 10991689, RettBASE proband ID: 4426, 6597, 6598) and another individual with Angelman syndrome-like phenotype (PMID 11283202) (PS4). Multiple pathogenic missense variants (p.Pro101His, p.Pro101Leu, p.Pro101Thr, p.Pro101Ser) have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11269512, RettBASE)(PM5_Strong). The p.Pro101Arg variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary the p.Pro101Arg variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS4, PM5_Strong, PM2_supporting, PP3).

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

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic ✓ concordant with ClinVar · top 7% in MECP2
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -14.68	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 886 bp · p 9.6e-08 · regional, not allelic
Overall
CADD	27.4	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 P101R vs ClinVar P113R) — 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.Pro113Arg
Coding: c.338C>G
MANE Select: NM_001110792
dbSNP: rs61754453
Type: single nucleotide variant
Location: chrX:154032282 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 101 UniProt numbering: the mbd domain; a β-strand; a UniProt-annotated variant site (in rtt); a UniProt-annotated variant site (in rtt; also in a patient with angelman syndrome and some typical rtt features); 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: Angelman syndrome 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.Pro113Ser Pathogenic ★★★ same residue
MECP2 p.Pro113His Likely pathogenic ★ same residue
MECP2 p.Pro113Leu Likely pathogenic ★ same residue
MECP2 p.Pro113fs Pathogenic ★ same residue
MECP2 p.Pro113Thr Likely 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

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-pro113arg (accessed [today's date]).

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