Is MECP2 p.Pro164Arg (c.491C>G) pathogenic?

MECP2 p.Pro164Arg (c.491C>G) is classified Pathogenic in MECP2 (ClinVar, Expert panel, 27 submitters; last evaluated 2021-10-26). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with Rett syndrome.

How common is MECP2 p.Pro164Arg (c.491C>G) in the general population?

MECP2 p.Pro164Arg (c.491C>G) is absent from gnomAD v4.1 (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.Pro164Arg (c.491C>G)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

MECP2 p.Pro164Arg

Q: What condition is associated with MECP2 p.Pro164Arg (c.491C>G)?

MECP2 p.Pro164Arg (c.491C>G) is associated with Rett syndrome, X-linked intellectual disability-psychosis-macroorchidism syndrome, syndromic X-linked intellectual disability Lubs type (ClinVar).

c.491C>G · rs61748404 · VCV143579

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 27 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Pathogenic for Rett syndrome. Applied ACMG criteria (verbatim):

PM6_VeryStrong PM2_Supporting PS3_Supporting PS4 PM1 PP3 PP4 PM5

Curation rationale (ClinGen, verbatim)

The p.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4).

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

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 5% in MECP2
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.1, 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 P152R vs ClinVar P164R) — 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.Pro164Arg
Coding: c.491C>G
MANE Select: NM_001110792
dbSNP: rs61748404
Type: single nucleotide variant
Location: chrX:154031373 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 152 UniProt numbering: the mbd domain; an α-helix; 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

Also linked: X-linked intellectual disability-psychosis-macroorchidism syndrome syndromic X-linked intellectual disability Lubs type autism, susceptibility to, X-linked 3 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.Pro164Ala Likely pathogenic ★★★ same residue
MECP2 p.Pro164Leu Pathogenic/Likely pathogenic ★★ same residue
MECP2 p.Pro164Thr Likely pathogenic ★ same residue
MECP2 p.Pro164fs Pathogenic ★ 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

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-pro164arg (accessed [today's date]).

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