Is MECP2 p.Arg262= (c.786C>A) pathogenic?

MECP2 p.Arg262= (c.786C>A) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-17). Very rare (popmax 0.00593%, eas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Arg262= (c.786C>A)?

MECP2 p.Arg262= (c.786C>A) is associated with severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Arg262= (c.786C>A) in the general population?

MECP2 p.Arg262= (c.786C>A) is very rare (popmax 0.00593%, eas) (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.Arg262=

c.786C>A · rs61748424 · VCV143680

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00593%, eas)

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 0.82	GERP -0.92, phastCons 1
Overall
CADD	5.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00593% East Asian · 2/33,755 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00851% 103/1,210,984 alleles · very rare exomes 89/1,098,102 · genomes 14/112,882 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.105%	955
Remaining individualsnot grpmax-eligible	0.0126%	7,939
East Asiangrpmax	0.00593%	16,877
African / African-American	0.00522%	19,173
European (non-Finnish)	0.00436%	22,956
Admixed American	0.00435%	23,007
South Asian	0.00351%	28,452

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg262=
Coding: c.786C>A
MANE Select: NM_001110792
dbSNP: rs61748424
Type: single nucleotide variant
Location: chrX:154031078 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 262: 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

Also linked: Rett syndrome

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Arg262Cys Benign ★★★ same residue
MECP2 p.Arg262His Likely benign ★★★ same residue
MECP2 p.Arg262fs Likely pathogenic ★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A Pathogenic ★★★ same condition
MECP2 c.62+2T>G Pathogenic ★★★ same condition
MECP2 p.Ala143Asp Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely 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-arg262 (accessed [today's date]).

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