Is ARX p.Ser463= (c.1389C>T) pathogenic?

ARX p.Ser463= (c.1389C>T) is classified Likely benign in ARX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-16). Very rare (popmax 0.00888%, amr); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Ser463= (c.1389C>T)?

ARX p.Ser463= (c.1389C>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.Ser463= (c.1389C>T) in the general population?

ARX p.Ser463= (c.1389C>T) is very rare (popmax 0.00888%, 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.

ARX p.Ser463=

c.1389C>T · rs760617042 · VCV1631996

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00888%, amr)

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 7.4	GERP 0.74, phastCons 1
Overall
CADD	14.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00888% Admixed American · 4/45,064 alleles

Filtering AF 0.00297% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00309% 37/1,196,365 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00888%	11,266
European (non-Finnish)	0.00371%	26,947

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.Ser463=
Coding: c.1389C>T
MANE Select: NM_139058
dbSNP: rs760617042
Type: single nucleotide variant
Location: chrX:25007170 (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.Ser463Asn Conflicting classifications of pathogenicity ★ ⚠ 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-ser463 (accessed [today's date]).

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