Is ARX p.Asp246= (c.738C>T) pathogenic?

ARX p.Asp246= (c.738C>T) is classified Benign in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-13). Ultra-rare (popmax 0.0162%, eas); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Asp246= (c.738C>T)?

ARX p.Asp246= (c.738C>T) is associated with developmental and epileptic encephalopathy, 1, intellectual disability, X-linked, with or without seizures, ARX-related (ClinVar).

How common is ARX p.Asp246= (c.738C>T) in the general population?

ARX p.Asp246= (c.738C>T) is ultra-rare (popmax 0.0162%, eas) (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.Asp246=

c.738C>T · rs750465338 · VCV1537856

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0162%, eas)

Conditions

developmental and epileptic encephalopathy, 1

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 0.46	GERP -0.48, phastCons 0.99
Overall
CADD	7.811	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0162% East Asian · 5/30,867 alleles

Filtering AF 0.00635% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00412%

Overall 0.000694% 8/1,152,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0162%	6,173
Remaining individualsnot grpmax-eligible	0.00438%	22,829
South Asian	0.0019%	52,521

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.Asp246=
Coding: c.738C>T
MANE Select: NM_139058
dbSNP: rs750465338
Type: single nucleotide variant
Location: chrX:25013257 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 246: the 'disordered' region

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.Asp246Glu 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
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-asp246 (accessed [today's date]).

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