Is ATRX p.Ser1326= (c.3978A>G) pathogenic?

ATRX p.Ser1326= (c.3978A>G) is classified Benign/Likely benign in ATRX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-12). Very rare (popmax 0.00626%, nfe); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Ser1326= (c.3978A>G)?

ATRX p.Ser1326= (c.3978A>G) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Ser1326= (c.3978A>G) in the general population?

ATRX p.Ser1326= (c.3978A>G) is very rare (popmax 0.00626%, nfe) (gnomAD).

ATRX p.Ser1326=

c.3978A>G · rs369658928 · VCV697834

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00626%, nfe)

Conditions

alpha thalassemia-X-linked intellectual disability syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -2.6, phastCons 0.98
Overall
CADD	8.169	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00626% European (non-Finnish) · 56/894,341 alleles

Filtering AF 0.00494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00444%

Overall 0.00496% 60/1,208,714 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00626%	15,970
Admixed American	0.00438%	22,834
Remaining individualsnot grpmax-eligible	0.0042%	23,781

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.Ser1326=
Coding: c.3978A>G
MANE Select: NM_000489
dbSNP: rs369658928
Type: single nucleotide variant
Location: chrX:77663524 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 1326: the 'disordered' region; the 'interaction with daxx' region; a modified residue (phosphoserine)

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 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-ser1326 (accessed [today's date]).

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