Is MECP2 p.Pro105Ser (c.313C>T) pathogenic?

MECP2 p.Pro105Ser (c.313C>T) is classified Conflicting classifications of pathogenicity in MECP2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-17). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with X-linked MECP2-related disorders.

What condition is associated with MECP2 p.Pro105Ser (c.313C>T)?

MECP2 p.Pro105Ser (c.313C>T) is associated with X-linked MECP2-related disorders, severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Pro105Ser (c.313C>T) in the general population?

MECP2 p.Pro105Ser (c.313C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MECP2 p.Pro105Ser (c.313C>T)?

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

MECP2 p.Pro105Ser

c.313C>T · rs61754447 · VCV143515

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked MECP2-related disorders

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 5% in MECP2
REVEL	0.686	pathogenic-leaning
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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	26.1	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 P93S vs ClinVar P105S) — 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.Pro105Ser
Coding: c.313C>T
MANE Select: NM_001110792
dbSNP: rs61754447
Type: single nucleotide variant
Location: chrX:154032307 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 93 UniProt numbering: the mbd domain; the 'disordered' region

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked MECP2-related disorders

Also linked: severe neonatal-onset encephalopathy with microcephaly Rett syndrome

Similar variants

MECP2 p.Pro105= Likely benign ★★ same residue
MECP2 p.Pro105fs 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
MECP2 p.Ala143Asp Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same condition
MECP2 p.Arg127His 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-pro105ser (accessed [today's date]).

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