Is MECP2 p.Pro397= (c.1191C>T) pathogenic?

MECP2 p.Pro397= (c.1191C>T) is classified Likely benign in MECP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-28). Very rare (popmax 0.00157%, nfe); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro397= (c.1191C>T)?

MECP2 p.Pro397= (c.1191C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro397= (c.1191C>T) in the general population?

MECP2 p.Pro397= (c.1191C>T) is very rare (popmax 0.00157%, nfe) (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.Pro397=

c.1191C>T · rs370226935 · VCV1082566

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00157%, nfe)

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 2.8	GERP 0.46, phastCons 1
Overall
CADD	3.688	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00157% European (non-Finnish) · 14/889,888 alleles

Filtering AF 0.000913% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000714%

Overall 0.00117% 14/1,198,561 alleles · very rare exomes 11/1,089,300 · genomes 3/109,261 · joint denominator

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.Pro397=
Coding: c.1191C>T
MANE Select: NM_001110792
dbSNP: rs370226935
Type: single nucleotide variant
Location: chrX:154030673 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 397: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in)

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.Pro397Ser Likely benign ★★★ same residue
MECP2 p.Pro397His Likely benign ★★ ⚠ same residue
MECP2 p.Pro397Arg Uncertain significance ★ ⚠ same residue
MECP2 p.Pro397Leu Likely benign ★ same residue
MECP2 p.Pro397Thr Likely benign ★ ⚠ same residue
MECP2 p.Pro397_Pro403del Uncertain significance ★★ same residue
MECP2 p.Pro397_Glu409delinsGlnGlnAsnSerProProTer Pathogenic ★ 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-pro397 (accessed [today's date]).

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