Is MECP2 p.Pro211Ser (c.631C>T) pathogenic?

MECP2 p.Pro211Ser (c.631C>T) is classified Benign in MECP2 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-02-28). AlphaMissense: likely benign (0.085); Ultra-rare (popmax 0.0118%, eas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro211Ser (c.631C>T)?

MECP2 p.Pro211Ser (c.631C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro211Ser (c.631C>T) in the general population?

MECP2 p.Pro211Ser (c.631C>T) is ultra-rare (popmax 0.0118%, eas) (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.Pro211Ser (c.631C>T)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

MECP2 p.Pro211Ser

c.631C>T · rs373329231 · VCV1604076

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Benign for Rett syndrome. Applied ACMG criteria (verbatim):

BS2 BS1

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the NM_004992.4: c.595C>T (p.Pro199Ser) variant in MECP2 in gnomAD v4.1 is 0.0002 in the East Asian population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The p.Pro199Ser variant is observed in at least 2 unaffected individuals (internal data, LabCorp Genetics Inc.) (BS2). The p.Pro199Ser variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Pro199Ser variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025).

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

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.43	indeterminate
SaProt	LLR -6.57	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 8.4	GERP 0.2, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	18.26	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 P199S vs ClinVar P211S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% East Asian · 4/33,756 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.000413% 5/1,209,679 alleles · ultra-rare exomes 4/1,098,264 · genomes 1/111,415 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0118%	8,439
Admixed American	0.00218%	45,832

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.Pro211Ser
Coding: c.631C>T
MANE Select: NM_001110792
dbSNP: rs373329231
Type: single nucleotide variant
Location: chrX:154031233 (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

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.Pro211Arg Likely benign ★★ same residue
MECP2 p.Pro211His 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-pro211ser (accessed [today's date]).

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