Is ARX p.Val198Ile (c.592G>A) pathogenic?

ARX p.Val198Ile (c.592G>A) is classified Uncertain significance in ARX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-20). AlphaMissense: likely benign (0.088); Very rare (popmax 0.00776%, eas); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Val198Ile (c.592G>A) in the general population?

ARX p.Val198Ile (c.592G>A) is very rare (popmax 0.00776%, eas) (gnomAD).

What do computational predictors say about ARX p.Val198Ile (c.592G>A)?

AlphaMissense predicts likely benign (score 0.088) — an in-silico prediction, not a clinical call.

ARX p.Val198Ile

Q: What condition is associated with ARX p.Val198Ile (c.592G>A)?

ARX p.Val198Ile (c.592G>A) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.592G>A · rs966816905 · VCV1356185

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00776%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked, with or without seizures, ARX-related

Computational evidence

Protein change
AlphaMissense	0.088	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -8.05	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 4.1	GERP -1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	17.4	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 0.00776% East Asian · 2/25,784 alleles

Filtering AF 0.00128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00048%

Overall 0.000561% 6/1,069,487 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00776%	12,892
European (non-Finnish)	0.000479%	208,632

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.Val198Ile
Coding: c.592G>A
MANE Select: NM_139058
dbSNP: rs966816905
Type: single nucleotide variant
Location: chrX:25013403 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 198: the 'disordered' region

Full ARX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked, with or without seizures, ARX-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 1

Similar variants

ARX p.Val198= Likely benign ★ same residue
ARX p.Val198fs Pathogenic ★ same residue
ARX p.Val198Ala 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

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-val198ile (accessed [today's date]).

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