Is ARX p.Ser174= (c.522G>T) pathogenic?

ARX p.Ser174= (c.522G>T) is classified Likely benign in ARX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-21). Ultra-rare (popmax 0.0467%, mid); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Ser174= (c.522G>T)?

ARX p.Ser174= (c.522G>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.Ser174= (c.522G>T) in the general population?

ARX p.Ser174= (c.522G>T) is ultra-rare (popmax 0.0467%, mid) (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.Ser174=

c.522G>T · rs2048711689 · VCV1198021

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, mid)

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 0.009	GERP -0.66, phastCons 0.9
Overall
CADD	13.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Middle Eastern · 1/2,142 alleles

Filtering AF 0.000197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000742% 6/808,304 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0467%	2,142
European (non-Finnish)	0.000674%	148,443

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.Ser174=
Coding: c.522G>T
MANE Select: NM_139058
dbSNP: rs2048711689
Type: single nucleotide variant
Location: chrX:25013473 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 174: 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.Ser174Leu 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-ser174 (accessed [today's date]).

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