Is MECP2 p.Pro110His (c.329C>A) pathogenic?

MECP2 p.Pro110His (c.329C>A) is classified Uncertain significance in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). AlphaMissense: likely pathogenic (0.9679); Absent from gnomAD v4.1; Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro110His (c.329C>A)?

MECP2 p.Pro110His (c.329C>A) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro110His (c.329C>A) in the general population?

MECP2 p.Pro110His (c.329C>A) is absent from gnomAD v4.1 (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MECP2 p.Pro110His (c.329C>A)?

AlphaMissense predicts likely pathogenic (score 0.9679) — an in-silico prediction, not a clinical call.

MECP2 p.Pro110His

c.329C>A · VCV4802230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9679 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.9679	likely pathogenic
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -10.45	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	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P98H vs ClinVar P110H) — 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.Pro110His
Coding: c.329C>A
MANE Select: NM_001110792
Type: single nucleotide variant
Location: chrX:154032291 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 98 UniProt numbering: the mbd domain; the 'disordered' region

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

Disease context

severe neonatal-onset encephalopathy with microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A 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
MECP2 p.Arg179Trp Pathogenic ★★★ same condition
MECP2 p.Arg267Pro 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-pro110his (accessed [today's date]).

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