Is MECP2 p.Pro399Ser (c.1195C>T) pathogenic?

MECP2 p.Pro399Ser (c.1195C>T) is classified Uncertain significance in MECP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0782); Very rare (popmax 0.00354%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro399Ser (c.1195C>T)?

MECP2 p.Pro399Ser (c.1195C>T) is associated with severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro399Ser (c.1195C>T) in the general population?

MECP2 p.Pro399Ser (c.1195C>T) is very rare (popmax 0.00354%, 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.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

MECP2 p.Pro399Ser

c.1195C>T · rs1171658384 · VCV941270

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00354%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.434	indeterminate
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	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	17.94	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 P387S vs ClinVar P399S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00354% South Asian · 2/56,486 alleles

Filtering AF 0.000587% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00022%

Overall 0.000647% 7/1,081,762 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00354%	28,243
Remaining individualsnot grpmax-eligible	0.00212%	47,075
African / African-American	0.00176%	56,721
European (non-Finnish)	0.000339%	294,760

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.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_001110792
dbSNP: rs1171658384
Type: single nucleotide variant
Location: chrX:154030669 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 387 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.Pro399Leu Benign ★★★ ⚠ same residue
MECP2 p.Pro399Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro399= Likely benign ★ same residue
MECP2 p.Pro399_Pro400insTer Pathogenic/Likely pathogenic ★★ 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

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-pro399ser (accessed [today's date]).

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