Is MECP2 p.Pro229Arg (c.686C>G) pathogenic?

MECP2 p.Pro229Arg (c.686C>G) is classified Uncertain significance in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: ambiguous (0.5034); Very rare (popmax 0.000447%, nfe).

How common is MECP2 p.Pro229Arg (c.686C>G) in the general population?

MECP2 p.Pro229Arg (c.686C>G) is very rare (popmax 0.000447%, nfe) (gnomAD).

What do computational predictors say about MECP2 p.Pro229Arg (c.686C>G)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

MECP2 p.Pro229Arg

c.686C>G · VCV4852692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.602	indeterminate
SaProt	LLR -8.18	tolerated
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	24.0	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 P217R vs ClinVar P229R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000447% European (non-Finnish) · 4/895,233 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000413% 5/1,210,936 alleles · very rare exomes 5/1,098,255 · genomes 0/112,681 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,643
European (non-Finnish)grpmax	0.000447%	223,808

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro229Arg
Coding: c.686C>G
MANE Select: NM_001110792
Type: single nucleotide variant
Location: chrX:154031178 (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

Similar variants

MECP2 p.Pro229Leu Likely pathogenic ★★★ ⚠ same residue
MECP2 p.Pro229Ser Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro229Ala Uncertain significance ★ ⚠ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same type
MECP2 c.62+1G>A Pathogenic ★★★ same type
MECP2 c.62+2T>G Pathogenic ★★★ same type
MECP2 p.Ala143Asp Pathogenic ★★★ same type
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same type

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-pro229arg (accessed [today's date]).

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