Is MECP2 p.Pro334= (c.1002C>T) pathogenic?

MECP2 p.Pro334= (c.1002C>T) is classified Benign in MECP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-16). Ultra-rare (popmax 0.0105%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro334= (c.1002C>T)?

MECP2 p.Pro334= (c.1002C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro334= (c.1002C>T) in the general population?

MECP2 p.Pro334= (c.1002C>T) is ultra-rare (popmax 0.0105%, sas) (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

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

MECP2 p.Pro334=

c.1002C>T · rs1165796985 · VCV2777998

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, sas)

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -2.5
Overall
CADD	4.465	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0105% South Asian · 6/56,902 alleles

Filtering AF 0.00458% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00165% 20/1,210,766 alleles · ultra-rare exomes 17/1,098,258 · genomes 3/112,508 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0105%	9,484
East Asian	0.00296%	33,793
Remaining individualsnot grpmax-eligible	0.0021%	47,609
European (non-Finnish)	0.00134%	74,614

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.Pro334=
Coding: c.1002C>T
MANE Select: NM_001110792
dbSNP: rs1165796985
Type: single nucleotide variant
Location: chrX:154030862 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 334: 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.Pro334Leu Pathogenic ★★★ same residue
MECP2 p.Pro334Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
MECP2 p.Pro334Ser Conflicting classifications of pathogenicity ★ ⚠ 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 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-pro334 (accessed [today's date]).

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