Is ARX p.Ala109= (c.327G>A) pathogenic?

ARX p.Ala109= (c.327G>A) is classified Likely benign in ARX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-01). Very rare (popmax 0.00374%, nfe); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Ala109= (c.327G>A)?

ARX p.Ala109= (c.327G>A) is associated with developmental and epileptic encephalopathy, 1, intellectual disability, X-linked, with or without seizures, ARX-related (ClinVar).

How common is ARX p.Ala109= (c.327G>A) in the general population?

ARX p.Ala109= (c.327G>A) is very rare (popmax 0.00374%, nfe) (gnomAD).

How is Infantile epileptic spasms syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ARX p.Ala109=

c.327G>A · rs1340239089 · VCV1103912

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00374%, nfe)

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	7.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00374% European (non-Finnish) · 25/667,698 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.0034% 27/793,642 alleles · very rare exomes 24/686,418 · genomes 3/107,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00395%	25,316
European (non-Finnish)grpmax	0.00374%	26,708
African / African-American	0.00229%	43,699

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: ARX
Protein: p.Ala109=
Coding: c.327G>A
MANE Select: NM_139058
dbSNP: rs1340239089
Type: single nucleotide variant
Location: chrX:25013668 (GRCh38)
Structure: AlphaFold pLDDT 56.51

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

Disease context

developmental and epileptic encephalopathy, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Infantile epileptic spasms syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant

Similar variants

ARX p.Ala109_Ala115dup Pathogenic/Likely pathogenic ★★ same residue
ARX p.Ala109_Ala115del Uncertain significance ★ same residue
ARX p.Ala109Thr Uncertain significance ★ ⚠ 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

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-ala109 (accessed [today's date]).

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