Is MECP2 p.Pro388Ser (c.1162C>T) pathogenic?

MECP2 p.Pro388Ser (c.1162C>T) is classified Benign in MECP2 (ClinVar, Expert panel, 17 submitters; last evaluated 2022-04-28). AlphaMissense: likely benign (0.0731); Rare (popmax 0.193%, eas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro388Ser (c.1162C>T)?

MECP2 p.Pro388Ser (c.1162C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro388Ser (c.1162C>T) in the general population?

MECP2 p.Pro388Ser (c.1162C>T) is rare (popmax 0.193%, 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.Pro388Ser (c.1162C>T)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

MECP2 p.Pro388Ser

c.1162C>T · rs61752387 · VCV95184

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.193%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS2 BA1

Curation rationale (ClinGen, verbatim)

The allele frequency of the c.1126C>T, p.(Pro376Ser) variant in MECP2 (NM_004992.4) is 0.13% in European (Non-Finnish) 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). The p.(Pro376Ser) variant is observed in at least 2 unaffected individuals (PMID 10944854, PMID 14560307, RettBASE) (BS1). In summary, the p.(Pro376Ser) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2).

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

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.48, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	17.15	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 P376S vs ClinVar P388S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.193% East Asian · 65/33,651 alleles

Filtering AF 0.168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.165%

Overall 0.147% 1,773/1,204,684 alleles · rare exomes 1,661/1,094,648 · genomes 112/110,036 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.193%	518
European (non-Finnish)	0.175%	571
Remaining individualsnot grpmax-eligible	0.158%	632
Finnishnot grpmax-eligible	0.0573%	1,746
African / African-American	0.0513%	1,950
Middle Eastern	0.0494%	2,026
South Asian	0.0142%	7,059
Admixed American	0.011%	9,103

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.Pro388Ser
Coding: c.1162C>T
MANE Select: NM_001110792
dbSNP: rs61752387
Type: single nucleotide variant
Location: chrX:154030702 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 376 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in)

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.Pro388Arg Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro388fs Likely 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

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-pro388ser (accessed [today's date]).

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