Is ARX p.Pro60Gln (c.179C>A) pathogenic?

ARX p.Pro60Gln (c.179C>A) is classified Uncertain significance in ARX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0578); Absent from gnomAD v4.1; Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

How common is ARX p.Pro60Gln (c.179C>A) in the general population?

ARX p.Pro60Gln (c.179C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARX p.Pro60Gln (c.179C>A)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

ARX p.Pro60Gln

Q: What condition is associated with ARX p.Pro60Gln (c.179C>A)?

ARX p.Pro60Gln (c.179C>A) is associated with intellectual disability, X-linked, with or without seizures, ARX-related, developmental and epileptic encephalopathy, 1 (ClinVar).

c.179C>A · VCV4788660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -6.99	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 3.4	GERP -0.52, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	11.91	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARX
Protein: p.Pro60Gln
Coding: c.179C>A
MANE Select: NM_139058
Type: single nucleotide variant
Location: chrX:25015559 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 60: 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.Pro60= Likely benign ★★ same residue
ARX p.Pro60Leu Uncertain significance ★ ⚠ same residue
ARX p.Pro60Arg 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

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-pro60gln (accessed [today's date]).

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