Is ARX p.Ala370Val (c.1109C>T) pathogenic?

ARX p.Ala370Val (c.1109C>T) is classified Uncertain significance in ARX (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-12). AlphaMissense: likely pathogenic (0.997); Very rare (popmax 0.000112%, nfe); Associated with intellectual disability, X-linked, with or without seizures, ARX-related.

What condition is associated with ARX p.Ala370Val (c.1109C>T)?

ARX p.Ala370Val (c.1109C>T) is associated with intellectual disability, X-linked, with or without seizures, ARX-related (ClinVar).

How common is ARX p.Ala370Val (c.1109C>T) in the general population?

ARX p.Ala370Val (c.1109C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about ARX p.Ala370Val (c.1109C>T)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

ARX p.Ala370Val

c.1109C>T · rs2519104171 · VCV3252939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic · top 10% in ARX
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -12.81	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 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 5,714 bp · p 1e-11 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000112% European (non-Finnish) · 1/894,740 alleles

Overall 9.11e-05% 1/1,097,781 alleles · very rare

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.Ala370Val
Coding: c.1109C>T
MANE Select: NM_139058
dbSNP: rs2519104171
Type: single nucleotide variant
Location: chrX:25010270 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 370: a DNA-binding region; a UniProt-annotated variant site (found in a patient with a neurodevelopmental disorder; uncertain significance)

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

Similar variants

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
ARX p.Pro353Leu Pathogenic ★★ same condition
ARX p.Ser319Ter 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-ala370val (accessed [today's date]).

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