Is MECP2 p.Pro211His (c.632C>A) pathogenic?

MECP2 p.Pro211His (c.632C>A) is classified Benign in MECP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-15). AlphaMissense: likely benign (0.1919); Ultra-rare (popmax 0.0456%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

How common is MECP2 p.Pro211His (c.632C>A) in the general population?

MECP2 p.Pro211His (c.632C>A) is ultra-rare (popmax 0.0456%, sas) (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.Pro211His (c.632C>A)?

AlphaMissense predicts likely benign (score 0.1919) — an in-silico prediction, not a clinical call.

MECP2 p.Pro211His

Q: What condition is associated with MECP2 p.Pro211His (c.632C>A)?

MECP2 p.Pro211His (c.632C>A) is associated with severe neonatal-onset encephalopathy with microcephaly, schizophrenia, Rett syndrome (ClinVar).

c.632C>A · rs267608502 · VCV143630

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1919 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0456%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.1919	likely benign
REVEL	0.416	indeterminate
SaProt	LLR -9.20	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 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	23.4	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 P199H vs ClinVar P211H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0456% South Asian · 26/56,962 alleles

Filtering AF 0.0319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00223% 27/1,211,680 alleles · ultra-rare exomes 27/1,098,263 · genomes 0/113,417 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0456%	2,191
Remaining individualsnot grpmax-eligible	0.0021%	47,652

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.Pro211His
Coding: c.632C>A
MANE Select: NM_001110792
dbSNP: rs267608502
Type: single nucleotide variant
Location: chrX:154031232 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 199 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: schizophrenia Rett syndrome

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro211Ser Benign ★★★ same residue
MECP2 p.Pro211Arg Likely benign ★★ same residue
MECP2 p.Pro211Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro211= Likely benign ★ same residue
MECP2 p.Pro211Leu 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-pro211his (accessed [today's date]).

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