Is ARX p.Ala440del (c.1300GCC[6]) pathogenic?

ARX p.Ala440del (c.1300GCC[6]) is classified Conflicting classifications of pathogenicity in ARX (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-02-02). Ultra-rare (popmax 0.0986%, amr); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Ala440del (c.1300GCC[6]) in the general population?

ARX p.Ala440del (c.1300GCC[6]) is ultra-rare (popmax 0.0986%, amr) (gnomAD).

ARX p.Ala440del

Q: What condition is associated with ARX p.Ala440del (c.1300GCC[6])?

ARX p.Ala440del (c.1300GCC[6]) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.1300GCC[6] · rs398124508 · VCV410779

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, amr)

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 · substitutions only
Constraint at this position
Conservation	phyloP 8.9	GERP 0.86, phastCons 1
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(GCG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0986% Admixed American · 32/32,461 alleles

Filtering AF 0.0718% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0626%

Overall 0.0152% 171/1,122,372 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0986%	1,014
East Asian	0.0416%	2,404
Finnishnot grpmax-eligible	0.0333%	3,003
African / African-American	0.0267%	3,751
Remaining individualsnot grpmax-eligible	0.0249%	4,009
South Asian	0.0212%	4,711
Ashkenazi Jewishnot grpmax-eligible	0.0154%	6,474
European (non-Finnish)	0.00898%	11,134

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.Ala440del
Coding: c.1300GCC[6]
MANE Select: NM_139058
dbSNP: rs398124508
Type: Microsatellite
Location: chrX:25007239 (GRCh38)
Structure: AlphaFold pLDDT 56.51

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.Ala440dup Benign/Likely benign ★★ same residue
ARX p.Ala440_Phe441insAlaAlaAlaAlaAla Uncertain significance ★ same residue
ARX p.Ala440= Likely benign ★ same residue
ARX p.Ala108_Ala115dup Pathogenic ★★ same condition
ARX p.220GT[3] Uncertain significance ★★ same condition
ARX p.Ala111_Ala115dup Uncertain significance ★★ same condition
ARX p.Ala113_Ala115dup Uncertain significance ★★ same condition
ARX p.Ala438_Ala440dup Uncertain significance ★★ 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-ala440del (accessed [today's date]).

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