Is ATRX p.Gln689Arg (c.2066A>G) pathogenic?

ATRX p.Gln689Arg (c.2066A>G) is classified Uncertain significance in ATRX (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.0786); Very rare (popmax 0.00437%, amr); Associated with alpha-thalassemia-myelodysplastic syndrome.

What condition is associated with ATRX p.Gln689Arg (c.2066A>G)?

ATRX p.Gln689Arg (c.2066A>G) is associated with alpha-thalassemia-myelodysplastic syndrome, alpha thalassemia-X-linked intellectual disability syndrome, intellectual disability-hypotonic facies syndrome, X-linked, 1 (ClinVar).

How common is ATRX p.Gln689Arg (c.2066A>G) in the general population?

ATRX p.Gln689Arg (c.2066A>G) is very rare (popmax 0.00437%, amr) (gnomAD).

How is Alpha-thalassemia-myelodysplastic syndrome inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ATRX p.Gln689Arg (c.2066A>G)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

ATRX p.Gln689Arg

c.2066A>G · rs929951326 · VCV450381

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00437%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alpha-thalassemia-myelodysplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -4.95	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 1.8	GERP -0.78, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	6.181	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 0.00437% Admixed American · 2/45,736 alleles

Filtering AF 0.000725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000271%

Overall 0.000331% 4/1,207,829 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00437%	22,868
Remaining individualsnot grpmax-eligible	0.0021%	47,516
European (non-Finnish)	0.000112%	893,248

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.Gln689Arg
Coding: c.2066A>G
MANE Select: NM_000489
dbSNP: rs929951326
Type: single nucleotide variant
Location: chrX:77683190 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 689: the 'disordered' region

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

Disease context

alpha-thalassemia-myelodysplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: alpha thalassemia-X-linked intellectual disability syndrome intellectual disability-hypotonic facies syndrome, X-linked, 1

For Alpha-thalassemia-myelodysplastic syndrome (Orphanet):

Inheritance: Not applicable
Onset: Adult

Similar variants

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
ATRX p.Arg2386Ter 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-gln689arg (accessed [today's date]).

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