Is MECP2 p.Arg180Pro (c.539G>C) pathogenic?

MECP2 p.Arg180Pro (c.539G>C) is classified Uncertain significance in MECP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-23). AlphaMissense: likely pathogenic (0.9939); Absent from gnomAD v4.1.

How common is MECP2 p.Arg180Pro (c.539G>C) in the general population?

MECP2 p.Arg180Pro (c.539G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MECP2 p.Arg180Pro (c.539G>C)?

AlphaMissense predicts likely pathogenic (score 0.9939) — an in-silico prediction, not a clinical call.

MECP2 p.Arg180Pro

c.539G>C · rs2522085385 · VCV2573814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9939 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9939	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	26.9	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 R168P vs ClinVar R180P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MECP2
Protein: p.Arg180Pro
Coding: c.539G>C
MANE Select: NM_001110792
dbSNP: rs2522085385
Type: single nucleotide variant
Location: chrX:154031325 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 168 UniProt numbering: the 'disordered' region

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MECP2 p.Arg180Ter Pathogenic ★★ same residue
MECP2 p.Arg180Gly Likely pathogenic ★ ⚠ same residue
MECP2 p.Arg180= Likely benign ★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same type
MECP2 c.62+1G>A Pathogenic ★★★ same type
MECP2 c.62+2T>G Pathogenic ★★★ same type
MECP2 p.Ala143Asp Pathogenic ★★★ same type
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same type

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-arg180pro (accessed [today's date]).

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