Is ARX p.Pro353Leu (c.1058C>T) pathogenic?

ARX p.Pro353Leu (c.1058C>T) is classified Pathogenic in ARX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with Partington syndrome.

How common is ARX p.Pro353Leu (c.1058C>T) in the general population?

ARX p.Pro353Leu (c.1058C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARX p.Pro353Leu (c.1058C>T)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

ARX p.Pro353Leu

Q: What condition is associated with ARX p.Pro353Leu (c.1058C>T)?

ARX p.Pro353Leu (c.1058C>T) is associated with Partington syndrome, corpus callosum agenesis-abnormal genitalia syndrome, X-linked lissencephaly with abnormal genitalia (ClinVar).

c.1058C>T · rs104894743 · VCV11188

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,206,061)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Partington syndrome

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 4% in ARX
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -13.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 5,714 bp · p 1e-11 · regional, not allelic
Overall
CADD	32.0	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

No allele count reported in gnomAD v4.1 (AN 1,206,061). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ARX
Protein: p.Pro353Leu
Coding: c.1058C>T
MANE Select: NM_139058
dbSNP: rs104894743
Type: single nucleotide variant
Location: chrX:25012937 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 353: a DNA-binding region; a UniProt-annotated variant site (in dee1; corpus callosum hypoplasia and simplified gyral pattern observed in one patient; reduces sequence-specific dna-binding; slightly reduces transcriptional repression of lmo1); a UniProt-annotated variant site (in lisx2; abolishes transcriptional activation of kdm5c; abolishes sequence-specific dna-binding; reduces transcriptional repression of lmo1 and shox2)

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

Disease context

Partington syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: corpus callosum agenesis-abnormal genitalia syndrome X-linked lissencephaly with abnormal genitalia intellectual disability, X-linked, with or without seizures, ARX-related developmental and epileptic encephalopathy, 1

Similar variants

ARX p.Pro353= Likely benign ★ same residue
ARX p.Arg330His Likely pathogenic ★★ same condition
ARX p.Arg332Cys Pathogenic/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

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-pro353leu (accessed [today's date]).

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