Is MECP2 p.Pro400Ser (c.1198C>T) pathogenic?

MECP2 p.Pro400Ser (c.1198C>T) is classified Benign in MECP2 (ClinVar, Expert panel, 12 submitters; last evaluated 2021-12-22). AlphaMissense: likely benign (0.0753); Ultra-rare (popmax 0.0132%, amr); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro400Ser (c.1198C>T)?

MECP2 p.Pro400Ser (c.1198C>T) is associated with Rett syndrome, intellectual disability, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro400Ser (c.1198C>T) in the general population?

MECP2 p.Pro400Ser (c.1198C>T) is ultra-rare (popmax 0.0132%, amr) (gnomAD).

How is Rett syndrome inherited?

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

What do computational predictors say about MECP2 p.Pro400Ser (c.1198C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

MECP2 p.Pro400Ser

c.1198C>T · rs61753000 · VCV143393

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Benign for Rett syndrome. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Pro388Ser (NM_004992.3) variant in MECP2 is 0.039% in a sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Pro388Ser variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -10.23	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	16.66	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 P388S vs ClinVar P400S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% Admixed American · 6/45,437 alleles

Filtering AF 0.00573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0039%

Overall 0.00543% 65/1,197,963 alleles · ultra-rare exomes 56/1,089,064 · genomes 9/108,899 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0132%	7,573
Ashkenazi Jewishnot grpmax-eligible	0.00912%	10,966
East Asian	0.00595%	16,804
European (non-Finnish)	0.00539%	18,541
African / African-American	0.00535%	18,699
Remaining individualsnot grpmax-eligible	0.00423%	23,649
Finnishnot grpmax-eligible	0.00235%	42,640
South Asian	0.00177%	56,428

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.Pro400Ser
Coding: c.1198C>T
MANE Select: NM_001110792
dbSNP: rs61753000
Type: single nucleotide variant
Location: chrX:154030666 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 388 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in); a UniProt-annotated variant site (in rtt; benign)

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

Also linked: intellectual disability severe neonatal-onset encephalopathy with microcephaly

For Rett syndrome (Orphanet):

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

Similar variants

MECP2 p.Pro400= Benign ★★★ same residue
MECP2 p.Pro400Leu Benign ★★★ same residue
MECP2 p.Pro400Ala Benign/Likely benign ★★ ⚠ same residue
MECP2 p.Pro400Thr Uncertain significance ★ ⚠ same residue
MECP2 p.Pro400_Pro479del Uncertain significance ★★★ same residue
MECP2 p.Pro400_Pro405del Likely benign ★★★ same residue
MECP2 p.Pro400fs Pathogenic ★★ same residue
MECP2 p.Pro400Ter Pathogenic ★★ same residue

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-pro400ser (accessed [today's date]).

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