Is ARX p.Ser11Cys (c.32C>G) pathogenic?

ARX p.Ser11Cys (c.32C>G) is classified Uncertain significance in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-07). AlphaMissense: likely benign (0.1761); Very rare (popmax 0.00175%, afr); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Ser11Cys (c.32C>G)?

ARX p.Ser11Cys (c.32C>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.Ser11Cys (c.32C>G) in the general population?

ARX p.Ser11Cys (c.32C>G) is very rare (popmax 0.00175%, afr) (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.Ser11Cys (c.32C>G)?

AlphaMissense predicts likely benign (score 0.1761) — an in-silico prediction, not a clinical call.

ARX p.Ser11Cys

c.32C>G · rs1698759878 · VCV2937380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
AlphaMissense	0.1761	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% African / African-American · 1/57,273 alleles

Overall 0.000888% 1/112,571 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.Ser11Cys
Coding: c.32C>G
MANE Select: NM_139058
dbSNP: rs1698759878
Type: single nucleotide variant
Location: chrX:25015706 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 11: 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.Ser11= Likely benign ★ 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-ser11cys (accessed [today's date]).

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