Is ARX p.Pro396Ala (c.1186C>G) pathogenic?

ARX p.Pro396Ala (c.1186C>G) is classified Uncertain significance in ARX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-06). AlphaMissense: likely benign (0.0604); Ultra-rare (popmax 0.0262%, mid); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with ARX p.Pro396Ala (c.1186C>G)?

ARX p.Pro396Ala (c.1186C>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.Pro396Ala (c.1186C>G) in the general population?

ARX p.Pro396Ala (c.1186C>G) is ultra-rare (popmax 0.0262%, 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.

What do computational predictors say about ARX p.Pro396Ala (c.1186C>G)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

ARX p.Pro396Ala

c.1186C>G · rs776523818 · VCV964299

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 1

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -5.65	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 8.3	GERP 0.004, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 2,715 bp · p 0.00019 · regional, not allelic
Overall
CADD	20.1	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 0.0262% Middle Eastern · 1/3,824 alleles

Filtering AF 0.000638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000239%

Overall 0.000868% 10/1,152,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0262%	3,824
Ashkenazi Jewishnot grpmax-eligible	0.00475%	21,033
South Asian	0.00385%	25,984
African / African-American	0.00184%	54,309
European (non-Finnish)	0.000574%	174,242

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.Pro396Ala
Coding: c.1186C>G
MANE Select: NM_139058
dbSNP: rs776523818
Type: single nucleotide variant
Location: chrX:25007373 (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.Pro396Thr 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-pro396ala (accessed [today's date]).

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