Is ARX p.Asp247His (c.739G>C) pathogenic?

ARX p.Asp247His (c.739G>C) is classified Likely benign in ARX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-24). AlphaMissense: likely pathogenic (0.5962); Very rare (popmax 0.00511%, amr); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Asp247His (c.739G>C)?

ARX p.Asp247His (c.739G>C) is associated with developmental and epileptic encephalopathy, 1, intellectual disability, X-linked, with or without seizures, ARX-related (ClinVar).

How common is ARX p.Asp247His (c.739G>C) in the general population?

ARX p.Asp247His (c.739G>C) is very rare (popmax 0.00511%, amr) (gnomAD).

How is Infantile epileptic spasms syndrome inherited?

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

What do computational predictors say about ARX p.Asp247His (c.739G>C)?

AlphaMissense predicts likely pathogenic (score 0.5962) — an in-silico prediction, not a clinical call.

ARX p.Asp247His

c.739G>C · rs765259012 · VCV1216161

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00511%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
AlphaMissense	0.5962	likely pathogenic
REVEL	0.281	benign-leaning
SaProt	LLR -12.12	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	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	24.2	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 0.00511% Admixed American · 2/39,151 alleles

Filtering AF 0.000846% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000317%

Overall 0.000192% 2/1,041,556 alleles · very rare

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.Asp247His
Coding: c.739G>C
MANE Select: NM_139058
dbSNP: rs765259012
Type: single nucleotide variant
Location: chrX:25013256 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 247: 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.Asp247Tyr 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-asp247his (accessed [today's date]).

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