Is MECP2 p.Pro492Ser (c.1474C>T) pathogenic?

MECP2 p.Pro492Ser (c.1474C>T) is classified Benign in MECP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-14). AlphaMissense: likely benign (0.2179); Very rare (popmax 0.00176%, sas); Associated with severe neonatal-onset encephalopathy with microcephaly.

What condition is associated with MECP2 p.Pro492Ser (c.1474C>T)?

MECP2 p.Pro492Ser (c.1474C>T) is associated with severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Pro492Ser (c.1474C>T) in the general population?

MECP2 p.Pro492Ser (c.1474C>T) is very rare (popmax 0.00176%, 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.Pro492Ser (c.1474C>T)?

AlphaMissense predicts likely benign (score 0.2179) — an in-silico prediction, not a clinical call.

MECP2 p.Pro492Ser

c.1474C>T · rs267608636 · VCV143477

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

severe neonatal-onset encephalopathy with microcephaly

Computational evidence

Protein change
AlphaMissense	0.2179	likely benign
REVEL	0.438	indeterminate
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	19.0	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 P480S vs ClinVar P492S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,725 alleles

Overall 0.000248% 3/1,209,666 alleles · very rare exomes 2/1,098,236 · genomes 1/111,430 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,620
South Asiangrpmax	0.00176%	56,725
European (non-Finnish)	0.000112%	895,111

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro492Ser
Coding: c.1474C>T
MANE Select: NM_001110792
dbSNP: rs267608636
Type: single nucleotide variant
Location: chrX:154030390 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 480 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in)

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

Also linked: Rett syndrome

For MECP2-related severe neonatal encephalopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MECP2 p.Pro492= Likely benign ★★ same residue
MECP2 p.Pro492Leu Uncertain significance ★ 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
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-pro492ser (accessed [today's date]).

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