Is MECP2 p.Pro57= (c.171C>T) pathogenic?

MECP2 p.Pro57= (c.171C>T) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-12). Ultra-rare (popmax 0.0246%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro57= (c.171C>T)?

MECP2 p.Pro57= (c.171C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro57= (c.171C>T) in the general population?

MECP2 p.Pro57= (c.171C>T) is ultra-rare (popmax 0.0246%, 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.Pro57=

c.171C>T · rs139477857 · VCV807856

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, 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 0.58	GERP -3.4, phastCons 0.99
Overall
CADD	3.445	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0246% South Asian · 14/56,942 alleles

Filtering AF 0.0148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00784% 95/1,211,174 alleles · ultra-rare exomes 79/1,097,992 · genomes 16/113,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0246%	4,067
Admixed American	0.0196%	5,112
Remaining individualsnot grpmax-eligible	0.0126%	7,941
African / African-American	0.0121%	8,237
European (non-Finnish)	0.00637%	15,709
Finnishnot grpmax-eligible	0.00429%	23,335

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.Pro57=
Coding: c.171C>T
MANE Select: NM_001110792
dbSNP: rs139477857
Type: single nucleotide variant
Location: chrX:154032449 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 57: 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.Pro57Ala 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
MECP2 p.Arg145Cys Pathogenic ★★★ same condition
MECP2 p.Arg145His Pathogenic ★★★ same condition
MECP2 p.Arg179Trp 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-pro57 (accessed [today's date]).

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