Is ARX p.Ala217Val (c.650C>T) pathogenic?

ARX p.Ala217Val (c.650C>T) is classified Uncertain significance in ARX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-08). AlphaMissense: likely benign (0.105); Very rare (popmax 0.000115%, nfe); Associated with Partington syndrome.

What condition is associated with ARX p.Ala217Val (c.650C>T)?

ARX p.Ala217Val (c.650C>T) is associated with Partington syndrome (ClinVar).

How common is ARX p.Ala217Val (c.650C>T) in the general population?

ARX p.Ala217Val (c.650C>T) is very rare (popmax 0.000115%, nfe) (gnomAD).

What do computational predictors say about ARX p.Ala217Val (c.650C>T)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

ARX p.Ala217Val

c.650C>T · VCV3338775

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000115%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Partington syndrome

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.91	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 4.3	GERP 0.53, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,633 bp · p 0.032 · regional, not allelic
Overall
CADD	16.15	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 0.000115% European (non-Finnish) · 1/870,264 alleles

Overall 9.64e-05% 1/1,037,210 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.Ala217Val
Coding: c.650C>T
MANE Select: NM_139058
Type: single nucleotide variant
Location: chrX:25013345 (GRCh38)
Structure: AlphaFold pLDDT 56.51
Residue 217: the 'disordered' region

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

Similar variants

ARX p.Ala217= Likely benign ★ same residue
ARX p.Arg332Gly Pathogenic/Likely pathogenic ★★ same condition
ARX p.Pro353Leu Pathogenic ★★ same condition
ARX p.Ala77Thr Uncertain significance ★★ ⚠ same condition
ARX p.Leu484Phe Uncertain significance ★★ ⚠ same condition
ARX p.Ala269= Benign/Likely benign ★★ same condition
ARX p.Ala63Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
ARX p.Arg87Pro Uncertain significance ★ ⚠ 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-ala217val (accessed [today's date]).

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