Is ARX p.Glu249Lys (c.745G>A) pathogenic?

ARX p.Glu249Lys (c.745G>A) is classified Uncertain significance in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely pathogenic (0.5816); Very rare (popmax 0.00358%, afr); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Glu249Lys (c.745G>A) in the general population?

ARX p.Glu249Lys (c.745G>A) is very rare (popmax 0.00358%, afr) (gnomAD).

What do computational predictors say about ARX p.Glu249Lys (c.745G>A)?

AlphaMissense predicts likely pathogenic (score 0.5816) — an in-silico prediction, not a clinical call.

ARX p.Glu249Lys

Q: What condition is associated with ARX p.Glu249Lys (c.745G>A)?

ARX p.Glu249Lys (c.745G>A) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.745G>A · VCV3749316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00358%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked, with or without seizures, ARX-related

Computational evidence

Protein change
AlphaMissense	0.5816	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	LLR -11.67	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00358% African / African-American · 2/55,843 alleles

Filtering AF 0.000594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000222%

Overall 0.00269% 3/111,551 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00358%	27,921
Admixed American	0.00256%	39,134

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: ARX
Protein: p.Glu249Lys
Coding: c.745G>A
MANE Select: NM_139058
Type: single nucleotide variant
Location: chrX:25013250 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 249: the 'disordered' region

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

Disease context

intellectual disability, X-linked, with or without seizures, ARX-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 1

Similar variants

ARX p.Glu249= Conflicting classifications of pathogenicity ★ same residue
ARX p.Arg330His Likely pathogenic ★★ same condition
ARX p.Arg332Gly Pathogenic/Likely pathogenic ★★ same condition
ARX p.Arg332His Pathogenic ★★ same condition
ARX p.Arg371Gln Likely pathogenic ★★ same condition
ARX p.Arg371Ter Pathogenic ★★ same condition
ARX p.Arg384Cys Pathogenic/Likely pathogenic ★★ same condition
ARX p.Glu294Ter 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/arx-p-glu249lys (accessed [today's date]).

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