Is MECP2 p.Ser385Pro (c.1153T>C) pathogenic?

MECP2 p.Ser385Pro (c.1153T>C) is classified Conflicting classifications of pathogenicity in MECP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-04-09). AlphaMissense: likely benign (0.0712); Very rare (popmax 0.00444%, amr); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Ser385Pro (c.1153T>C)?

MECP2 p.Ser385Pro (c.1153T>C) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Ser385Pro (c.1153T>C) in the general population?

MECP2 p.Ser385Pro (c.1153T>C) is very rare (popmax 0.00444%, amr) (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

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

What do computational predictors say about MECP2 p.Ser385Pro (c.1153T>C)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

MECP2 p.Ser385Pro

c.1153T>C · rs782420258 · VCV632887

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00444%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.009	GERP -3.1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	4.468	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 S373P vs ClinVar S385P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00444% Admixed American · 2/45,066 alleles

Filtering AF 0.000736% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000275%

Overall 0.000666% 8/1,200,345 alleles · very rare exomes 6/1,095,183 · genomes 2/105,162 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00444%	22,533
Remaining individualsnot grpmax-eligible	0.00211%	47,377
African / African-American	0.00183%	54,752
European (non-Finnish)	0.000449%	222,849

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.Ser385Pro
Coding: c.1153T>C
MANE Select: NM_001110792
dbSNP: rs782420258
Type: single nucleotide variant
Location: chrX:154030711 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 373 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

severe neonatal-onset encephalopathy with microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Ser385Ter Pathogenic ★★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same condition
MECP2 p.Arg127His Pathogenic ★★★ same condition
MECP2 p.Arg145Cys Pathogenic ★★★ same condition
MECP2 p.Arg145His Pathogenic ★★★ same condition
MECP2 p.Arg179Trp 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-ser385pro (accessed [today's date]).

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