Is MECP2 p.Pro185Thr (c.553C>A) pathogenic?

MECP2 p.Pro185Thr (c.553C>A) is classified Uncertain significance in MECP2 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-08-30). AlphaMissense: likely benign (0.1292); Very rare (popmax 0.000223%, nfe); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro185Thr (c.553C>A)?

MECP2 p.Pro185Thr (c.553C>A) is associated with Rett syndrome (ClinVar).

How common is MECP2 p.Pro185Thr (c.553C>A) in the general population?

MECP2 p.Pro185Thr (c.553C>A) is very rare (popmax 0.000223%, 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.Pro185Thr (c.553C>A)?

AlphaMissense predicts likely benign (score 0.1292) — an in-silico prediction, not a clinical call.

MECP2 p.Pro185Thr

c.553C>A · rs61748427 · VCV804125

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Uncertain Significance for Rett syndrome. Applied ACMG criteria (verbatim):

BS2_Supporting

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the p.Pro173Thr variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.000002233 in European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro173Thr variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2_Supporting). The p.Pro173Thr variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Pro173Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2_Supporting). (MECP2 specification v3.0.0, curation approved on 8/30/2024)

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

Computational evidence

Protein change
AlphaMissense	0.1292	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.2, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	23.3	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 P173T vs ClinVar P185T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000223% European (non-Finnish) · 2/895,591 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000248% 3/1,212,058 alleles · very rare exomes 3/1,098,243 · genomes 0/113,815 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,651
European (non-Finnish)grpmax	0.000223%	447,796

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.Pro185Thr
Coding: c.553C>A
MANE Select: NM_001110792
dbSNP: rs61748427
Type: single nucleotide variant
Location: chrX:154031311 (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

For Rett syndrome (Orphanet):

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

Similar variants

MECP2 p.Pro185Ala Likely benign ★★★ same residue
MECP2 p.Pro185Arg 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-pro185thr (accessed [today's date]).

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