Is MECP2 p.His63Gln (c.189C>G) pathogenic?

MECP2 p.His63Gln (c.189C>G) is classified Uncertain significance in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.097); Very rare (popmax 0.000112%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.His63Gln (c.189C>G)?

MECP2 p.His63Gln (c.189C>G) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.His63Gln (c.189C>G) in the general population?

MECP2 p.His63Gln (c.189C>G) is very rare (popmax 0.000112%, nfe) (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.His63Gln (c.189C>G)?

AlphaMissense predicts likely benign (score 0.097) — an in-silico prediction, not a clinical call.

MECP2 p.His63Gln

c.189C>G · rs267608432 · VCV143493

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.097 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Uncertain Significance for Rett syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting BS2_Supporting

Curation rationale (ClinGen, verbatim)

The p.His51Gln variant in MECP2 (NM_004992.4) is absent from gnomAD v4.1 (PM2_Supporting). However, the p.His51Gln variant is observed in at least 1 unaffected individual (PMID 21300488) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.His51Gln variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). (MECP2 Specifications v.4.1; curation approved on [5/7/2025])

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

Computational evidence

Protein change
AlphaMissense	0.097	likely benign
REVEL	0.434	indeterminate
SaProt	LLR -4.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 65 kb · p 0.54 · regional, not allelic
Overall
CADD	13.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 H51Q vs ClinVar H63Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/895,530 alleles

Overall 8.25e-05% 1/1,212,314 alleles · very rare exomes 1/1,097,987 · genomes 0/114,327 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MECP2
Protein: p.His63Gln
Coding: c.189C>G
MANE Select: NM_001110792
dbSNP: rs267608432
Type: single nucleotide variant
Location: chrX:154032431 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 51 UniProt numbering: 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: 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.His63= Benign/Likely benign ★★ 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
MECP2 p.Arg145Cys 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-his63gln (accessed [today's date]).

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