Is MECP2 p.Pro391Ser (c.1171C>T) pathogenic?

MECP2 p.Pro391Ser (c.1171C>T) is classified Benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.0668); Ultra-rare (popmax 0.0159%, sas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro391Ser (c.1171C>T)?

MECP2 p.Pro391Ser (c.1171C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro391Ser (c.1171C>T) in the general population?

MECP2 p.Pro391Ser (c.1171C>T) is ultra-rare (popmax 0.0159%, sas) (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.Pro391Ser (c.1171C>T)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

MECP2 p.Pro391Ser

c.1171C>T · rs782050077 · VCV1170846

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0159%, sas)

Missense predictors

0/2 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):

BS2 BS1 BP5

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Pro379Ser variant in MECP2 (NM_004992.3) is 0.017% in African sub population in gnomAD v2, 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). The p.Pro379Ser variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro379Ser variant is found in at least 3 patients with an alternate molecular basis of disease (internal database - GeneDx, internal database - Invitae) (BP5). In summary, the p.Pro379Ser variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5).

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

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	13.42	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 P379S vs ClinVar P391S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0159% South Asian · 9/56,432 alleles

Filtering AF 0.00828% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00621%

Overall 0.00374% 45/1,203,029 alleles · ultra-rare exomes 39/1,093,224 · genomes 6/109,805 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0159%	6,270
Admixed American	0.0132%	7,575
East Asian	0.00891%	11,217
Ashkenazi Jewishnot grpmax-eligible	0.00456%	21,908
Remaining individualsnot grpmax-eligible	0.00422%	23,679
African / African-American	0.00355%	28,188
European (non-Finnish)	0.00247%	40,565

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.Pro391Ser
Coding: c.1171C>T
MANE Select: NM_001110792
dbSNP: rs782050077
Type: single nucleotide variant
Location: chrX:154030693 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 379 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: 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.Pro391Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro391= Likely benign ★ same residue
MECP2 p.Pro391fs Pathogenic ★★ 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-pro391ser (accessed [today's date]).

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