Is MECP2 p.Pro229Ser (c.685C>T) pathogenic?

MECP2 p.Pro229Ser (c.685C>T) is classified Uncertain significance in MECP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: likely benign (0.0909); Very rare (popmax 0.00176%, sas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro229Ser (c.685C>T)?

MECP2 p.Pro229Ser (c.685C>T) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Pro229Ser (c.685C>T) in the general population?

MECP2 p.Pro229Ser (c.685C>T) is very rare (popmax 0.00176%, sas) (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.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

MECP2 p.Pro229Ser

c.685C>T · rs786205894 · VCV192293

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rett syndrome

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -6.12	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 9.8	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	20.3	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 P217S vs ClinVar P229S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,850 alleles

Filtering AF 0.000241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000158%

Overall 0.000637% 7/1,098,262 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,850
European (non-Finnish)	0.00067%	149,200

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.Pro229Ser
Coding: c.685C>T
MANE Select: NM_001110792
dbSNP: rs786205894
Type: single nucleotide variant
Location: chrX:154031179 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 217 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

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MECP2 p.Pro229Leu Likely pathogenic ★★★ ⚠ same residue
MECP2 p.Pro229Ala Uncertain significance ★ ⚠ same residue
MECP2 p.Pro229Arg Uncertain significance ★ 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

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-pro229ser (accessed [today's date]).

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