Is MECP2 p.Pro415Ser (c.1243C>T) pathogenic?

MECP2 p.Pro415Ser (c.1243C>T) is classified Conflicting classifications of pathogenicity in MECP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-28). AlphaMissense: likely benign (0.0899); Very rare (popmax 0.00296%, eas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro415Ser (c.1243C>T)?

MECP2 p.Pro415Ser (c.1243C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro415Ser (c.1243C>T) in the general population?

MECP2 p.Pro415Ser (c.1243C>T) is very rare (popmax 0.00296%, eas) (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.Pro415Ser (c.1243C>T)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

MECP2 p.Pro415Ser

c.1243C>T · rs782495086 · VCV2122595

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -5.38	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 8.2	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	16.82	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 P403S vs ClinVar P415S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00296% East Asian · 1/33,812 alleles

Overall 0.000414% 5/1,206,572 alleles · very rare exomes 5/1,094,053 · genomes 0/112,519 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00296%	33,812
Remaining individualsnot grpmax-eligible	0.0021%	47,557
South Asian	0.00176%	56,852
African / African-American	0.00174%	57,459
European (non-Finnish)	0.000112%	894,791

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.Pro415Ser
Coding: c.1243C>T
MANE Select: NM_001110792
dbSNP: rs782495086
Type: single nucleotide variant
Location: chrX:154030621 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 403 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.Pro415Leu Likely benign ★★★ same residue
MECP2 p.Pro415Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro415His Uncertain significance ★ ⚠ same residue
MECP2 p.Pro415Thr Uncertain significance ★ ⚠ same residue
MECP2 p.Pro415fs Pathogenic ★ same residue
MECP2 p.Pro415del Uncertain significance ★ same residue
MECP2 p.Pro415Arg Likely benign ★★★ same residue
MECP2 c.414-3C>G 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-pro415ser (accessed [today's date]).

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