Is MECP2 p.Pro188Arg (c.563C>G) pathogenic?

MECP2 p.Pro188Arg (c.563C>G) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-12). AlphaMissense: ambiguous (0.5555); Ultra-rare (popmax 0.0592%, eas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro188Arg (c.563C>G)?

MECP2 p.Pro188Arg (c.563C>G) is associated with severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Pro188Arg (c.563C>G) in the general population?

MECP2 p.Pro188Arg (c.563C>G) is ultra-rare (popmax 0.0592%, eas) (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.Pro188Arg (c.563C>G)?

AlphaMissense predicts ambiguous (score 0.5555) — an in-silico prediction, not a clinical call.

MECP2 p.Pro188Arg

c.563C>G · rs61749701 · VCV143611

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0592%, eas)

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.5555	ambiguous
REVEL	0.441	indeterminate
SaProt	LLR -11.93	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	26.3	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 P176R vs ClinVar P188R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0592% East Asian · 20/33,776 alleles

Filtering AF 0.0392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0328%

Overall 0.00603% 73/1,210,508 alleles · ultra-rare exomes 69/1,098,237 · genomes 4/112,271 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0592%	1,689
European (non-Finnish)	0.00547%	18,271
African / African-American	0.00349%	28,670
Admixed American	0.00218%	45,886
Remaining individualsnot grpmax-eligible	0.0021%	47,621

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.Pro188Arg
Coding: c.563C>G
MANE Select: NM_001110792
dbSNP: rs61749701
Type: single nucleotide variant
Location: chrX:154031301 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 176 UniProt numbering: 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

Also linked: Rett syndrome

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro188= Likely benign ★★★ same residue
MECP2 p.Pro188His Likely benign ★★★ ⚠ same residue
MECP2 p.Pro188Leu Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro188Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro188Ala 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

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-pro188arg (accessed [today's date]).

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