Is MECP2 p.Pro68= (c.204C>T) pathogenic?

MECP2 p.Pro68= (c.204C>T) is classified Benign in MECP2 (ClinVar, Expert panel, 9 submitters; last evaluated 2021-12-13). Rare (popmax 0.209%, sas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro68= (c.204C>T)?

MECP2 p.Pro68= (c.204C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro68= (c.204C>T) in the general population?

MECP2 p.Pro68= (c.204C>T) is rare (popmax 0.209%, sas) (gnomAD).

How is Rett syndrome inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

MECP2 p.Pro68=

c.204C>T · rs61754435 · VCV143496

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.209%, sas)

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BA1

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Pro56= (NM_004992.3) variant in MECP2 is 0.231% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro56= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -3.4
Overall
CADD	4.376	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.209% South Asian · 119/56,947 alleles

Filtering AF 0.178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0164% 199/1,211,199 alleles · rare exomes 186/1,097,992 · genomes 13/113,207 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.209%	479
African / African-American	0.0173%	5,766
Admixed American	0.0109%	9,207
Remaining individualsnot grpmax-eligible	0.0105%	9,528
East Asian	0.00888%	11,265
European (non-Finnish)	0.00625%	15,988
Finnishnot grpmax-eligible	0.00214%	46,722

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.Pro68=
Coding: c.204C>T
MANE Select: NM_001110792
dbSNP: rs61754435
Type: single nucleotide variant
Location: chrX:154032416 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 68: 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.Pro68fs Pathogenic ★ 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
MECP2 p.Arg127His Pathogenic ★★★ same condition
MECP2 p.Arg145Cys 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-pro68 (accessed [today's date]).

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