Is MECP2 p.Pro415Arg (c.1244C>G) pathogenic?

MECP2 p.Pro415Arg (c.1244C>G) is classified Likely benign in MECP2 (ClinVar, Expert panel, 4 submitters; last evaluated 2023-12-06). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.000335%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro415Arg (c.1244C>G)?

MECP2 p.Pro415Arg (c.1244C>G) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Pro415Arg (c.1244C>G) in the general population?

MECP2 p.Pro415Arg (c.1244C>G) is very rare (popmax 0.000335%, nfe) (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.Pro415Arg (c.1244C>G)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

MECP2 p.Pro415Arg

c.1244C>G · rs587783107 · VCV1212000

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000335%, nfe)

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

Curation rationale (ClinGen, verbatim)

The p.Pro403Arg variant in MECP2 (NM_004992.4) is present in 3 XX and 2 XY individual(s) in gnomAD (0.0003564%) (not sufficient to meet BS1 criteria). The p.Pro403Arg variant is observed in 3 unaffected individuals (internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro403Arg variant in MECP2 (NM_004992.4) is classified as likely benign based on the ACMG/AMP criteria (BS2).

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

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.434	indeterminate
SaProt	LLR -7.08	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 6.2	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	18.07	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 P403R vs ClinVar P415R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000335% European (non-Finnish) · 3/894,822 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000249% 3/1,206,923 alleles · very rare exomes 3/1,094,103 · genomes 0/112,820 · 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.Pro415Arg
Coding: c.1244C>G
MANE Select: NM_001110792
dbSNP: rs587783107
Type: single nucleotide variant
Location: chrX:154030620 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 403 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

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MECP2 p.Pro415Leu Likely benign ★★★ same residue
MECP2 p.Pro415_Glu416insTer Pathogenic ★ same residue
MECP2 p.Pro415Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro415His Uncertain significance ★ ⚠ same residue
MECP2 p.Pro415Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MECP2 p.Pro415Thr 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-pro415arg (accessed [today's date]).

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