Is MECP2 p.Arg306Pro (c.917G>C) pathogenic?

MECP2 p.Arg306Pro (c.917G>C) is classified Likely benign in MECP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-01). AlphaMissense: likely benign (0.247); Very rare (popmax 0.00175%, sas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Arg306Pro (c.917G>C)?

MECP2 p.Arg306Pro (c.917G>C) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Arg306Pro (c.917G>C) in the general population?

MECP2 p.Arg306Pro (c.917G>C) is very rare (popmax 0.00175%, 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.Arg306Pro (c.917G>C)?

AlphaMissense predicts likely benign (score 0.247) — an in-silico prediction, not a clinical call.

MECP2 p.Arg306Pro

c.917G>C · rs61751366 · VCV143724

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Rett syndrome

Computational evidence

Protein change
AlphaMissense	0.247	likely benign
REVEL	0.537	indeterminate
SaProt	LLR -4.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	21.6	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 R294P vs ClinVar R306P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% South Asian · 1/57,032 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000495% 6/1,212,073 alleles · very rare exomes 6/1,098,232 · genomes 0/113,841 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00175%	57,032
European (non-Finnish)	0.000558%	179,109

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.Arg306Pro
Coding: c.917G>C
MANE Select: NM_001110792
dbSNP: rs61751366
Type: single nucleotide variant
Location: chrX:154030947 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 294 UniProt numbering: the 'interaction with ncor2' region; a UniProt-annotated variant site (in rtt); the 'interaction with tbl1xr1' 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.Arg306Ter Pathogenic ★★★ same residue
MECP2 p.Arg306fs Likely pathogenic ★ same residue
MECP2 p.Arg306= Benign/Likely benign ★★ same residue
MECP2 p.Arg306Gln Likely benign ★★ same residue
MECP2 p.Arg306Gly Likely benign ★ 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

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-arg306pro (accessed [today's date]).

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