Is MECP2 p.Arg480= (c.1440G>A) pathogenic?

MECP2 p.Arg480= (c.1440G>A) is classified Likely benign in MECP2 (ClinVar, Expert panel, 7 submitters; last evaluated 2022-05-10). Very rare (popmax 0.00257%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Arg480= (c.1440G>A)?

MECP2 p.Arg480= (c.1440G>A) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Arg480= (c.1440G>A) in the general population?

MECP2 p.Arg480= (c.1440G>A) is very rare (popmax 0.00257%, nfe) (gnomAD).

How is Rett syndrome inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

MECP2 p.Arg480=

c.1440G>A · rs267608633 · VCV138196

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00257%, nfe)

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for Rett syndrome. Applied ACMG criteria (verbatim):

BP5 BP7 BP4

Curation rationale (ClinGen, verbatim)

The silent p.Arg468= variant in MECP2 (NM_004992) is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). The p.Arg468= variant is found in two patients with an alternate molecular basis of disease (INVITAE internal cases) (BP5). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary the p.Arg468= variant in MECP2 is classified as Likely Benign for Rett syndrome disorder based on the ACMG/AMP criteria (BP7, BP4, BP5).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Overall
CADD	12.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00257% European (non-Finnish) · 23/894,933 alleles

Filtering AF 0.00171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.0019% 23/1,209,034 alleles · very rare exomes 22/1,098,195 · genomes 1/110,839 · 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.Arg480=
Coding: c.1440G>A
MANE Select: NM_001110792
dbSNP: rs267608633
Type: single nucleotide variant
Location: chrX:154030424 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 480: 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

Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe neonatal-onset encephalopathy with microcephaly

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MECP2 p.Arg480Thr Benign ★ ⚠ same residue
MECP2 p.Arg480_Pro481del Uncertain significance ★ 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
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-arg480 (accessed [today's date]).

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