Is MECP2 p.Pro393Ser (c.1177C>T) pathogenic?

MECP2 p.Pro393Ser (c.1177C>T) is classified Likely benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.0723); Very rare (popmax 0.00357%, afr); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro393Ser (c.1177C>T)?

MECP2 p.Pro393Ser (c.1177C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro393Ser (c.1177C>T) in the general population?

MECP2 p.Pro393Ser (c.1177C>T) is very rare (popmax 0.00357%, afr) (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.Pro393Ser (c.1177C>T)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

MECP2 p.Pro393Ser

c.1177C>T · rs61752981 · VCV431897

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00357%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS2 BP5

Curation rationale (ClinGen, verbatim)

The p.Pro381Ser variant in MECP2 (NM_004992.4) is observed in at least 19 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro381Ser variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Pro381Ser variant in MECP2 in gnomAD v4.1 is 0.00003574 in the African/African American population (not sufficient to meet BS1 criteria). In summary, the p.Pro381Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5).

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

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -6.71	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 7.2	GERP 0.49, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	10.96	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 P381S vs ClinVar P393S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00357% African / African-American · 2/55,961 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00217% 26/1,200,382 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00357%	27,980
European (non-Finnish)	0.00258%	38,766
Finnishnot grpmax-eligible	0.00228%	43,773

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.Pro393Ser
Coding: c.1177C>T
MANE Select: NM_001110792
dbSNP: rs61752981
Type: single nucleotide variant
Location: chrX:154030687 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 381 UniProt numbering: a UniProt-annotated variant site (in rtt); 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.Pro393Ala Uncertain significance ★ ⚠ same residue
MECP2 p.Pro393= Likely benign ★ same residue
MECP2 p.Pro393fs Pathogenic ★ same residue
MECP2 p.Pro393Leu 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

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-pro393ser (accessed [today's date]).

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