Is ARX p.Ala499Pro (c.1495G>C) pathogenic?

ARX p.Ala499Pro (c.1495G>C) is classified Uncertain significance in ARX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.5802); Very rare (popmax 0.00612%, nfe); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Ala499Pro (c.1495G>C) in the general population?

ARX p.Ala499Pro (c.1495G>C) is very rare (popmax 0.00612%, nfe) (gnomAD).

What do computational predictors say about ARX p.Ala499Pro (c.1495G>C)?

AlphaMissense predicts likely pathogenic (score 0.5802) — an in-silico prediction, not a clinical call.

ARX p.Ala499Pro

Q: What condition is associated with ARX p.Ala499Pro (c.1495G>C)?

ARX p.Ala499Pro (c.1495G>C) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.1495G>C · rs2147318769 · VCV1427413

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00612%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5802	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 0.92, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 2,715 bp · p 0.00019 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00612% European (non-Finnish) · 53/866,268 alleles

Filtering AF 0.00477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00433%

Overall 0.00479% 55/1,147,049 alleles · very rare exomes 55/1,033,054 · genomes 0/113,995 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00612%	16,345
Remaining individualsnot grpmax-eligible	0.00447%	22,356

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.Ala499Pro
Coding: c.1495G>C
MANE Select: NM_139058
dbSNP: rs2147318769
Type: single nucleotide variant
Location: chrX:25004864 (GRCh38)
Structure: AlphaFold pLDDT 56.51

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.Ala499Val Uncertain significance ★ ⚠ same residue
ARX p.Ala499= Likely benign ★ same residue
ARX p.Ala499Thr 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-ala499pro (accessed [today's date]).

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