Is ATRX p.Pro1296= (c.3888A>G) pathogenic?

ATRX p.Pro1296= (c.3888A>G) is classified Benign in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). Ultra-rare (popmax 0.0105%, afr); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Pro1296= (c.3888A>G)?

ATRX p.Pro1296= (c.3888A>G) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Pro1296= (c.3888A>G) in the general population?

ATRX p.Pro1296= (c.3888A>G) is ultra-rare (popmax 0.0105%, afr) (gnomAD).

ATRX p.Pro1296=

c.3888A>G · rs139540415 · VCV1169515

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, afr)

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 1.6	GERP -1.5, phastCons 1
Overall
CADD	8.048	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0105% African / African-American · 6/57,147 alleles

Filtering AF 0.00456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00307%

Overall 0.000662% 8/1,208,895 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0105%	9,525
Remaining individualsnot grpmax-eligible	0.00421%	23,780

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.Pro1296=
Coding: c.3888A>G
MANE Select: NM_000489
dbSNP: rs139540415
Type: single nucleotide variant
Location: chrX:77664700 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 1296: the 'disordered' region; the 'interaction with daxx' region

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-pro1296 (accessed [today's date]).

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