Is MECP2 p.Pro401Ser (c.1201C>T) pathogenic?

MECP2 p.Pro401Ser (c.1201C>T) is classified Uncertain significance in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.000112%, nfe).

How common is MECP2 p.Pro401Ser (c.1201C>T) in the general population?

MECP2 p.Pro401Ser (c.1201C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about MECP2 p.Pro401Ser (c.1201C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

MECP2 p.Pro401Ser

c.1201C>T · VCV4953503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -12.20	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 4.8	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	14.58	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 P389S vs ClinVar P401S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/888,950 alleles

Overall 8.36e-05% 1/1,196,295 alleles · very rare exomes 0/1,087,937 · genomes 1/108,358 · joint denominator

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.Pro401Ser
Coding: c.1201C>T
MANE Select: NM_001110792
Type: single nucleotide variant
Location: chrX:154030663 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 389 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

Similar variants

MECP2 p.Pro401Arg Uncertain significance ★ ⚠ same residue
MECP2 p.Pro401= Likely benign ★ same residue
MECP2 p.Pro401_Pro417delinsTer Pathogenic/Likely pathogenic ★★ same residue
MECP2 p.Pro401_Pro403del Uncertain significance ★★ same residue
MECP2 p.Pro401_Ser407delinsTer Pathogenic ★ same residue
MECP2 p.Pro401fs Pathogenic ★ same residue
MECP2 p.Pro401_Ser407del Uncertain significance ★ same residue
MECP2 p.Pro401_Ser408del Uncertain significance ★ 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-pro401ser (accessed [today's date]).

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