Is MECP2 p.Phe154= (c.462C>T) pathogenic?

MECP2 p.Phe154= (c.462C>T) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-13). Rare (popmax 0.114%, mid); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Phe154= (c.462C>T)?

MECP2 p.Phe154= (c.462C>T) is associated with severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Phe154= (c.462C>T) in the general population?

MECP2 p.Phe154= (c.462C>T) is rare (popmax 0.114%, mid) (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.Phe154=

c.462C>T · rs61748397 · VCV95195

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.114%, mid)

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 6.5	GERP 1.1, phastCons 1
Overall
CADD	10.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.114% Middle Eastern · 5/4,374 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0407% 492/1,209,664 alleles · rare exomes 470/1,097,569 · genomes 22/112,095 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.114%	875
South Asian	0.0598%	1,672
East Asian	0.0532%	1,878
European (non-Finnish)	0.0433%	2,312
Admixed American	0.0306%	3,271
Remaining individualsnot grpmax-eligible	0.0294%	3,398
African / African-American	0.0227%	4,401
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,343
Finnishnot grpmax-eligible	0.00858%	11,658

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.Phe154=
Coding: c.462C>T
MANE Select: NM_001110792
dbSNP: rs61748397
Type: single nucleotide variant
Location: chrX:154031402 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 154: the mbd domain; an α-helix; 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.Phe154Leu 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
MECP2 p.Arg145Cys 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-phe154 (accessed [today's date]).

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