Is MECP2 p.Pro185Arg (c.554C>G) pathogenic?

MECP2 p.Pro185Arg (c.554C>G) is classified Likely benign in MECP2 (ClinVar, Expert panel, 8 submitters; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.7177); Very rare (popmax 0.00528%, sas); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro185Arg (c.554C>G)?

MECP2 p.Pro185Arg (c.554C>G) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro185Arg (c.554C>G) in the general population?

MECP2 p.Pro185Arg (c.554C>G) is very rare (popmax 0.00528%, 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.Pro185Arg (c.554C>G)?

AlphaMissense predicts likely pathogenic (score 0.7177) — an in-silico prediction, not a clinical call.

MECP2 p.Pro185Arg

c.554C>G · rs267608492 · VCV143609

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00528%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

PP3 BS2 BP5

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the p.Pro173Arg variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.00005278 in the South Asian population (not sufficient to meet BS1 criteria). The p.Pro173Arg variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Pro173Arg variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro173Arg variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). (MECP2 Specifications v.4.1; curation approved on [5/7/2025])

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

Computational evidence

Protein change
AlphaMissense	0.7177	likely pathogenic
REVEL	0.644	pathogenic-leaning
SaProt	LLR -10.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.24, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	26.0	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 P173R vs ClinVar P185R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00528% South Asian · 3/56,838 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000688%

Overall 0.000909% 11/1,210,509 alleles · very rare exomes 10/1,098,243 · genomes 1/112,266 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00528%	18,946
Remaining individualsnot grpmax-eligible	0.0021%	47,610
African / African-American	0.00175%	57,281
European (non-Finnish)	0.00067%	149,219

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.Pro185Arg
Coding: c.554C>G
MANE Select: NM_001110792
dbSNP: rs267608492
Type: single nucleotide variant
Location: chrX:154031310 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 173 UniProt numbering: 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.Pro185Thr Uncertain significance ★★★ ⚠ same residue
MECP2 p.Pro185Ala Likely benign ★★★ same residue
MECP2 p.Pro185His Uncertain significance ★ ⚠ 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-pro185arg (accessed [today's date]).

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