Is MECP2 p.Pro334Ser (c.1000C>T) pathogenic?

MECP2 p.Pro334Ser (c.1000C>T) is classified Conflicting classifications of pathogenicity in MECP2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-07-15). AlphaMissense: likely benign (0.2783); Absent from gnomAD v4.1; Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro334Ser (c.1000C>T)?

MECP2 p.Pro334Ser (c.1000C>T) is associated with severe neonatal-onset encephalopathy with microcephaly, X-linked intellectual disability-psychosis-macroorchidism syndrome, Rett syndrome (ClinVar).

How common is MECP2 p.Pro334Ser (c.1000C>T) in the general population?

MECP2 p.Pro334Ser (c.1000C>T) is absent from gnomAD v4.1 (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.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.2783) — an in-silico prediction, not a clinical call.

MECP2 p.Pro334Ser

c.1000C>T · rs61751449 · VCV11843

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2783 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.2783	likely benign
REVEL	0.51	indeterminate
SaProt	LLR -7.14	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	23.1	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 P322S vs ClinVar P334S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MECP2
Protein: p.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_001110792
dbSNP: rs61751449
Type: single nucleotide variant
Location: chrX:154030864 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 322 UniProt numbering: a UniProt-annotated variant site (in rtt); a UniProt-annotated variant site (in mrxs13)

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

Also linked: X-linked intellectual disability-psychosis-macroorchidism syndrome Rett syndrome

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro334Leu Pathogenic ★★★ same residue
MECP2 p.Pro334Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
MECP2 p.Pro334= Benign ★ same residue
MECP2 p.Pro334_Leu335del Uncertain significance ★ same residue
MECP2 p.Pro334His 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

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-pro334ser (accessed [today's date]).

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