Is ARX p.Pro353= (c.1059G>A) pathogenic?

ARX p.Pro353= (c.1059G>A) is classified Likely benign in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). Ultra-rare (popmax 0.0283%, mid); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Pro353= (c.1059G>A) in the general population?

ARX p.Pro353= (c.1059G>A) is ultra-rare (popmax 0.0283%, mid) (gnomAD).

ARX p.Pro353=

Q: What condition is associated with ARX p.Pro353= (c.1059G>A)?

ARX p.Pro353= (c.1059G>A) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.1059G>A · rs1060504804 · VCV416370

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, mid)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.6	GERP -4.2
Overall
CADD	3.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Middle Eastern · 1/3,534 alleles

Overall 0.000275% 3/1,091,710 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0283%	3,534
Remaining individualsnot grpmax-eligible	0.00211%	47,383
African / African-American	0.00173%	57,869

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.Pro353=
Coding: c.1059G>A
MANE Select: NM_139058
dbSNP: rs1060504804
Type: single nucleotide variant
Location: chrX:25012936 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 353: a DNA-binding region; a UniProt-annotated variant site (in dee1; corpus callosum hypoplasia and simplified gyral pattern observed in one patient; reduces sequence-specific dna-binding; slightly reduces transcriptional repression of lmo1); a UniProt-annotated variant site (in lisx2; abolishes transcriptional activation of kdm5c; abolishes sequence-specific dna-binding; reduces transcriptional repression of lmo1 and shox2)

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.Pro353Leu Pathogenic ★★ 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-pro353 (accessed [today's date]).

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