Is MECP2 p.Pro417= (c.1251C>T) pathogenic?

MECP2 p.Pro417= (c.1251C>T) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-04). Ultra-rare (popmax 0.0445%, eas); Associated with Inborn genetic diseases.

What condition is associated with MECP2 p.Pro417= (c.1251C>T)?

MECP2 p.Pro417= (c.1251C>T) is associated with Inborn genetic diseases, severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Pro417= (c.1251C>T) in the general population?

MECP2 p.Pro417= (c.1251C>T) is ultra-rare (popmax 0.0445%, eas) (gnomAD).

MECP2 p.Pro417=

c.1251C>T · rs61753964 · VCV143440

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0445%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.224	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.98, phastCons 1
Overall
CADD	7.483	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0445% East Asian · 15/33,683 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0221%

Overall 0.00823% 99/1,203,270 alleles · ultra-rare exomes 90/1,094,526 · genomes 9/108,744 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0445%	2,246
Remaining individualsnot grpmax-eligible	0.0147%	6,787
European (non-Finnish)	0.00805%	12,416
South Asian	0.00707%	14,136
Finnishnot grpmax-eligible	0.00232%	43,086

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.Pro417=
Coding: c.1251C>T
MANE Select: NM_001110792
dbSNP: rs61753964
Type: single nucleotide variant
Location: chrX:154030613 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 417: 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

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

Also linked: severe neonatal-onset encephalopathy with microcephaly Rett syndrome

Similar variants

MECP2 p.Pro417Leu Benign ★★★ same residue
MECP2 p.Pro417Ser Likely benign ★ same residue
MECP2 p.Pro417fs Pathogenic/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-pro417 (accessed [today's date]).

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