Is MECP2 p.Pro113Ser (c.337C>T) pathogenic?

MECP2 p.Pro113Ser (c.337C>T) is classified Pathogenic in MECP2 (ClinVar, Expert panel, 4 submitters; last evaluated 2021-03-26). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro113Ser (c.337C>T)?

MECP2 p.Pro113Ser (c.337C>T) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Pro113Ser (c.337C>T) in the general population?

MECP2 p.Pro113Ser (c.337C>T) 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.Pro113Ser (c.337C>T)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

MECP2 p.Pro113Ser

c.337C>T · rs61754452 · VCV143524

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9995 · 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 PM1 PP3 PP4

Curation rationale (ClinGen, verbatim)

The p.Pro101Ser variant has been observed in at least 4 other individuals with Rett syndrome (RettBASE, internal database) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10767337, 31439979) (PM5_Strong). The p.Pro101Ser 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). The p.Pro101Ser variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 11269512) (PP4). In summary, the p.Pro101Ser variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM5_strong, PM2_supporting, PP3, PP4).

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

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 5% in MECP2
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -12.81	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	26.4	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 P101S vs ClinVar P113S) — 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.Pro113Ser
Coding: c.337C>T
MANE Select: NM_001110792
dbSNP: rs61754452
Type: single nucleotide variant
Location: chrX:154032283 (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

For Rett syndrome (Orphanet):

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

Similar variants

MECP2 p.Pro113Arg 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-pro113ser (accessed [today's date]).

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