Is MECP2 p.Pro417Ser (c.1249C>T) pathogenic?

MECP2 p.Pro417Ser (c.1249C>T) is classified Likely benign in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.1664); Very rare (popmax 0.00531%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro417Ser (c.1249C>T)?

MECP2 p.Pro417Ser (c.1249C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro417Ser (c.1249C>T) in the general population?

MECP2 p.Pro417Ser (c.1249C>T) is very rare (popmax 0.00531%, sas) (gnomAD).

How is MECP2-related severe neonatal encephalopathy inherited?

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

What do computational predictors say about MECP2 p.Pro417Ser (c.1249C>T)?

AlphaMissense predicts likely benign (score 0.1664) — an in-silico prediction, not a clinical call.

MECP2 p.Pro417Ser

c.1249C>T · rs781786825 · VCV1129106

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00531%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.1664	likely benign
REVEL	0.452	indeterminate
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P405S vs ClinVar P417S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00531% South Asian · 3/56,535 alleles

Filtering AF 0.00141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00069%

Overall 0.000915% 11/1,202,646 alleles · very rare exomes 10/1,094,459 · genomes 1/108,187 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00531%	18,845
Remaining individualsnot grpmax-eligible	0.00421%	23,745
Admixed American	0.00221%	45,342
European (non-Finnish)	0.000559%	178,766

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.Pro417Ser
Coding: c.1249C>T
MANE Select: NM_001110792
dbSNP: rs781786825
Type: single nucleotide variant
Location: chrX:154030615 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 405 UniProt numbering: 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

severe neonatal-onset encephalopathy with microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro417Leu Benign ★★★ same residue
MECP2 p.Pro417= Benign/Likely benign ★★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same condition
MECP2 p.Arg127His Pathogenic ★★★ same condition
MECP2 p.Arg145Cys Pathogenic ★★★ same condition
MECP2 p.Arg145His 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-pro417ser (accessed [today's date]).

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