Is MECP2 p.Pro373Ser (c.1117C>T) pathogenic?

MECP2 p.Pro373Ser (c.1117C>T) is classified Likely benign in MECP2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-04-18). AlphaMissense: likely benign (0.0612); Very rare (popmax 0.00176%, sas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro373Ser (c.1117C>T)?

MECP2 p.Pro373Ser (c.1117C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro373Ser (c.1117C>T) in the general population?

MECP2 p.Pro373Ser (c.1117C>T) is very rare (popmax 0.00176%, 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.Pro373Ser (c.1117C>T)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

MECP2 p.Pro373Ser

c.1117C>T · rs61752373 · VCV655951

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS2 BP5

Curation rationale (ClinGen, verbatim)

The p.Pro361Ser variant in MECP2 (NM_004992.3) is present in 9 XX and 3 XY individual(s) in gnomAD v4.0 (0.001%) (not sufficient to meet BS1 criteria). The p.Pro361Ser variant in the MECP2 gene is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro361Ser variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). In summary, the p.Pro361Ser variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5).

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

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -4.33	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 8	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	17.3	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 P361S vs ClinVar P373S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,727 alleles

Filtering AF 0.000473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000993% 12/1,208,408 alleles · very rare exomes 11/1,097,522 · genomes 1/110,886 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,532
South Asiangrpmax	0.00176%	56,727
African / African-American	0.00176%	56,808
European (non-Finnish)	0.00101%	99,390

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.Pro373Ser
Coding: c.1117C>T
MANE Select: NM_001110792
dbSNP: rs61752373
Type: single nucleotide variant
Location: chrX:154030747 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 361 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.Pro373Ala Benign ★★★ same residue
MECP2 p.Pro373His Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro373= Likely benign ★ same residue
MECP2 p.Pro373Leu Likely benign ★ same residue
MECP2 p.Pro373Thr Conflicting classifications of pathogenicity ★ same residue
MECP2 p.Pro373Arg Uncertain significance ★ ⚠ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A 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-pro373ser (accessed [today's date]).

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