Is MECP2 p.Pro431Ser (c.1291C>T) pathogenic?

MECP2 p.Pro431Ser (c.1291C>T) is classified Benign in MECP2 (ClinVar, Expert panel, 9 submitters; last evaluated 2022-04-28). AlphaMissense: likely benign (0.0871); Ultra-rare (popmax 0.0154%, amr); Associated with Rett syndrome.

How common is MECP2 p.Pro431Ser (c.1291C>T) in the general population?

MECP2 p.Pro431Ser (c.1291C>T) is ultra-rare (popmax 0.0154%, 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.Pro431Ser (c.1291C>T)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

MECP2 p.Pro431Ser

Q: What condition is associated with MECP2 p.Pro431Ser (c.1291C>T)?

MECP2 p.Pro431Ser (c.1291C>T) is associated with Rett syndrome, X-linked intellectual disability-psychosis-macroorchidism syndrome, syndromic X-linked intellectual disability Lubs type (ClinVar).

c.1291C>T · rs140258520 · VCV156634

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

PS4_Supporting BS2 BS1 BP5

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Pro419Ser variant in MECP2 (NM_004992.3) is 0.02% in "Other" sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1) and additionally is present in three male individuals in gnomAD. The p.Pro419Ser variant is observed in at least 7 unaffected individuals (Baylor Genetic internal database, GeneDx internal database, PMID 16225173) (BS2). The p.Pro419Ser variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro419Ser variant has been observed in at least 2 individuals with neurodevelopmental disorders (PMID 32457807, 16225173) (PS4_supporting), however in these studies MECP2 was the only gene sequenced. In summary the p.Pro419Ser variant in MECP2 is classified as benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5) and the PS4_supporting evidence is not considered inconsistent with the final benign classification.

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

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.474	indeterminate
SaProt	LLR -5.54	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 4.3	GERP -0.81, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	16.98	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 P419S vs ClinVar P431S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% Admixed American · 7/45,572 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00532%

Overall 0.00655% 79/1,206,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0154%	6,510
Remaining individualsnot grpmax-eligible	0.0105%	9,510
European (non-Finnish)	0.00727%	13,762
East Asian	0.00297%	33,709
African / African-American	0.00177%	56,599

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.Pro431Ser
Coding: c.1291C>T
MANE Select: NM_001110792
dbSNP: rs140258520
Type: single nucleotide variant
Location: chrX:154030573 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 419 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

Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked intellectual disability-psychosis-macroorchidism syndrome syndromic X-linked intellectual disability Lubs type autism, susceptibility to, X-linked 3 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.Pro431Leu Benign ★★★ same residue
MECP2 p.Pro431= Benign/Likely benign ★★ same residue
MECP2 p.Pro431Ala 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

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-pro431ser (accessed [today's date]).

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