Is ATRX p.Arg246= (c.738C>T) pathogenic?

ATRX p.Arg246= (c.738C>T) is classified Likely benign in ATRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-02). Very rare (popmax 0.00699%, afr); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Arg246= (c.738C>T)?

ATRX p.Arg246= (c.738C>T) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Arg246= (c.738C>T) in the general population?

ATRX p.Arg246= (c.738C>T) is very rare (popmax 0.00699%, afr) (gnomAD).

ATRX p.Arg246=

c.738C>T · rs781856746 · VCV1078060

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00699%, 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 3.9	GERP 0.26, phastCons 1
Overall
CADD	9.396	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00699% African / African-American · 4/57,242 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.000331% 4/1,208,768 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.Arg246=
Coding: c.738C>T
MANE Select: NM_000489
dbSNP: rs781856746
Type: single nucleotide variant
Location: chrX:77684518 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 246: the add domain; a UniProt-annotated variant site (in atrx; impairs interaction with histone h3 peptides trimethylated at 'lys-10' (h3k9me3) and reduces localization to pericentromeric heterochromatin foci); a UniProt-annotated variant site (in atrx; impairs interaction with histone h3 peptides trimethylated at 'lys-10' (h3k9me3)); an α-helix

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.Arg246Cys Pathogenic/Likely pathogenic ★★ same residue
ATRX p.Arg246Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ATRX p.Arg246Gly Likely pathogenic ★ same residue
ATRX p.Arg246His 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

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-arg246 (accessed [today's date]).

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