Is MECP2 p.Pro399= (c.1197C>G) pathogenic?

MECP2 p.Pro399= (c.1197C>G) is classified Likely benign in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). Very rare (popmax 0.0022%, amr); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro399= (c.1197C>G)?

MECP2 p.Pro399= (c.1197C>G) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro399= (c.1197C>G) in the general population?

MECP2 p.Pro399= (c.1197C>G) is very rare (popmax 0.0022%, 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.

MECP2 p.Pro399=

c.1197C>G · rs61750246 · VCV3005690

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, amr)

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 3.3	GERP -2.1, phastCons 1
Overall
CADD	3.606	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% Admixed American · 1/45,413 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000334% 4/1,197,251 alleles · very rare exomes 3/1,088,400 · genomes 1/108,851 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0022%	45,413
European (non-Finnish)	0.000337%	296,469

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.Pro399=
Coding: c.1197C>G
MANE Select: NM_001110792
dbSNP: rs61750246
Type: single nucleotide variant
Location: chrX:154030667 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 399: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in mrxs13; likely benign)

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.Pro399Leu Benign ★★★ ⚠ same residue
MECP2 p.Pro399Ser Uncertain significance ★★ ⚠ same residue
MECP2 p.Pro399Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro399_Pro400insTer Pathogenic/Likely 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

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-pro399 (accessed [today's date]).

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