Is ARX p.Pro53Arg (c.158C>G) pathogenic?

ARX p.Pro53Arg (c.158C>G) is classified Conflicting classifications of pathogenicity in ARX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-19). AlphaMissense: ambiguous (0.3572); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Pro53Arg (c.158C>G)?

ARX p.Pro53Arg (c.158C>G) is associated with developmental and epileptic encephalopathy, 1, intellectual disability, X-linked, with or without seizures, ARX-related (ClinVar).

How common is ARX p.Pro53Arg (c.158C>G) in the general population?

ARX p.Pro53Arg (c.158C>G) is absent from gnomAD v4.1 (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.Pro53Arg (c.158C>G)?

AlphaMissense predicts ambiguous (score 0.3572) — an in-silico prediction, not a clinical call.

ARX p.Pro53Arg

c.158C>G · rs1329228660 · VCV663519

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3572 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
AlphaMissense	0.3572	ambiguous
REVEL	0.485	indeterminate
SaProt	LLR -7.43	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARX
Protein: p.Pro53Arg
Coding: c.158C>G
MANE Select: NM_139058
dbSNP: rs1329228660
Type: single nucleotide variant
Location: chrX:25015580 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 53: 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.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
ARX p.Pro353Leu 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-pro53arg (accessed [today's date]).

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