Is ARX p.Arg257Pro (c.770G>C) pathogenic?

ARX p.Arg257Pro (c.770G>C) is classified Conflicting classifications of pathogenicity in ARX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.1708); Very rare (popmax 0.00248%, amr); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Arg257Pro (c.770G>C)?

ARX p.Arg257Pro (c.770G>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.Arg257Pro (c.770G>C) in the general population?

ARX p.Arg257Pro (c.770G>C) is very rare (popmax 0.00248%, 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.Arg257Pro (c.770G>C)?

AlphaMissense predicts likely benign (score 0.1708) — an in-silico prediction, not a clinical call.

ARX p.Arg257Pro

c.770G>C · rs1239494313 · VCV1530059

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00248%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
AlphaMissense	0.1708	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.66, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	16.95	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 0.00248% Admixed American · 1/40,303 alleles

Overall 9.55e-05% 1/1,047,519 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.Arg257Pro
Coding: c.770G>C
MANE Select: NM_139058
dbSNP: rs1239494313
Type: single nucleotide variant
Location: chrX:25013225 (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.Arg257His Uncertain significance ★★ ⚠ same residue
ARX p.Arg257= Conflicting classifications of pathogenicity ★ same residue
ARX p.Arg257Cys Uncertain significance ★ ⚠ same residue
ARX p.Arg257Gly 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

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-arg257pro (accessed [today's date]).

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