Is MECP2 p.Val331Met (c.991G>A) pathogenic?

MECP2 p.Val331Met (c.991G>A) is classified Uncertain significance in MECP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-16). AlphaMissense: likely benign (0.1183); Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Lubs type.

What condition is associated with MECP2 p.Val331Met (c.991G>A)?

MECP2 p.Val331Met (c.991G>A) is associated with syndromic X-linked intellectual disability Lubs type, X-linked intellectual disability-psychosis-macroorchidism syndrome, autism, susceptibility to, X-linked 3 (ClinVar).

How common is MECP2 p.Val331Met (c.991G>A) in the general population?

MECP2 p.Val331Met (c.991G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MECP2 p.Val331Met (c.991G>A)?

AlphaMissense predicts likely benign (score 0.1183) — an in-silico prediction, not a clinical call.

MECP2 p.Val331Met

c.991G>A · rs1569548388 · VCV625979

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1183 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

syndromic X-linked intellectual disability Lubs type

Computational evidence

Protein change
AlphaMissense	0.1183	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	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	19.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V319M vs ClinVar V331M) — 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.Val331Met
Coding: c.991G>A
MANE Select: NM_001110792
dbSNP: rs1569548388
Type: single nucleotide variant
Location: chrX:154030873 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 319 UniProt numbering: a UniProt-annotated variant site (in rtt)

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

Disease context

syndromic X-linked intellectual disability Lubs type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked intellectual disability-psychosis-macroorchidism syndrome autism, susceptibility to, X-linked 3 severe neonatal-onset encephalopathy with microcephaly Rett syndrome

Similar variants

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
MECP2 p.Arg127His Pathogenic ★★★ same condition
MECP2 p.Arg145Cys Pathogenic ★★★ same condition
MECP2 p.Arg145His 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-val331met (accessed [today's date]).

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