Is MECP2 p.Lys375Ter (c.1123A>T) pathogenic?

MECP2 p.Lys375Ter (c.1123A>T) is classified Pathogenic in MECP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-14). Absent from gnomAD v4.1; Associated with Rett syndrome.

What condition is associated with MECP2 p.Lys375Ter (c.1123A>T)?

MECP2 p.Lys375Ter (c.1123A>T) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Lys375Ter (c.1123A>T) in the general population?

MECP2 p.Lys375Ter (c.1123A>T) is absent from gnomAD v4.1 (gnomAD).

How is Rett syndrome inherited?

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

MECP2 p.Lys375Ter

c.1123A>T · rs61752375 · VCV143326

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Rett syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MECP2
Protein: p.Lys375Ter
Coding: c.1123A>T
MANE Select: NM_001110792
dbSNP: rs61752375
Type: single nucleotide variant
Location: chrX:154030741 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 375: a UniProt-annotated variant site (in rtt); the 'disordered' region

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

For Rett syndrome (Orphanet):

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

Similar variants

MECP2 p.Lys375fs Likely pathogenic ★ same residue
MECP2 p.Lys375Thr Uncertain significance ★★ same residue
MECP2 p.Lys375= Likely benign ★ same residue
MECP2 p.Lys375Asn Likely benign ★ ⚠ 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

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-lys375ter (accessed [today's date]).

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