Is MECP2 p.Val257= (c.771C>G) pathogenic?

MECP2 p.Val257= (c.771C>G) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0498%, amr); Associated with Inborn genetic diseases.

What condition is associated with MECP2 p.Val257= (c.771C>G)?

MECP2 p.Val257= (c.771C>G) is associated with Inborn genetic diseases, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Val257= (c.771C>G) in the general population?

MECP2 p.Val257= (c.771C>G) is ultra-rare (popmax 0.0498%, amr) (gnomAD).

MECP2 p.Val257=

c.771C>G · rs782027467 · VCV413770

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0498%, amr)

Conditions

Inborn genetic diseases

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 5.7	GERP 0.24, phastCons 1
Overall
CADD	6.454	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0498% Admixed American · 23/46,144 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0288%

Overall 0.0028% 34/1,212,283 alleles · ultra-rare exomes 34/1,098,212 · genomes 0/114,071 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0498%	2,006
European (non-Finnish)	0.00123%	81,419

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.Val257=
Coding: c.771C>G
MANE Select: NM_001110792
dbSNP: rs782027467
Type: single nucleotide variant
Location: chrX:154031093 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 257: the 'disordered' region

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe neonatal-onset encephalopathy with microcephaly

Similar variants

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
MECP2 p.Arg267Pro 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-val257 (accessed [today's date]).

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