Is ATRX p.Ala2389Val (c.7166C>T) pathogenic?

ATRX p.Ala2389Val (c.7166C>T) is classified Uncertain significance in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-12). AlphaMissense: ambiguous (0.3638); Very rare (popmax 0.000336%, nfe); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Ala2389Val (c.7166C>T)?

ATRX p.Ala2389Val (c.7166C>T) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Ala2389Val (c.7166C>T) in the general population?

ATRX p.Ala2389Val (c.7166C>T) is very rare (popmax 0.000336%, nfe) (gnomAD).

What do computational predictors say about ATRX p.Ala2389Val (c.7166C>T)?

AlphaMissense predicts ambiguous (score 0.3638) — an in-silico prediction, not a clinical call.

ATRX p.Ala2389Val

c.7166C>T · rs1401922551 · VCV2898158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000336%, nfe)

Conditions

alpha thalassemia-X-linked intellectual disability syndrome

Computational evidence

Protein change
AlphaMissense	0.3638	ambiguous
REVEL	0.483	indeterminate
SaProt	LLR -8.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 14 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	24.8	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 0.000336% European (non-Finnish) · 3/893,725 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000274% 3/1,096,018 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: ATRX
Protein: p.Ala2389Val
Coding: c.7166C>T
MANE Select: NM_000489
dbSNP: rs1401922551
Type: single nucleotide variant
Location: chrX:77520822 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB

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

Disease context

alpha thalassemia-X-linked intellectual disability syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATRX p.Ala2389Thr Uncertain significance ★ same residue
ATRX c.5449-7A>G Likely pathogenic ★★ same condition
ATRX p.Arg1022Ter Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg1661Cys Likely pathogenic ★★ ⚠ same condition
ATRX p.Arg2085Cys Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg2085His Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg2131Gln Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg2178Trp 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/atrx-p-ala2389val (accessed [today's date]).

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