Is ATRX p.Arg658= (c.1974T>G) pathogenic?

ATRX p.Arg658= (c.1974T>G) is classified Conflicting classifications of pathogenicity in ATRX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-04-06). Very rare (popmax 0.000112%, nfe); Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with ATRX p.Arg658= (c.1974T>G)?

ATRX p.Arg658= (c.1974T>G) is associated with intellectual disability-hypotonic facies syndrome, X-linked, 1, alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Arg658= (c.1974T>G) in the general population?

ATRX p.Arg658= (c.1974T>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

ATRX p.Arg658=

c.1974T>G · rs1603222314 · VCV699023

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

intellectual disability-hypotonic facies syndrome, X-linked, 1

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 1.4	GERP -4.4, phastCons 1
Overall
CADD	7.484	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/894,575 alleles

Overall 9.12e-05% 1/1,097,006 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.Arg658=
Coding: c.1974T>G
MANE Select: NM_000489
dbSNP: rs1603222314
Type: single nucleotide variant
Location: chrX:77683282 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 658: the 'disordered' region

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

Disease context

intellectual disability-hypotonic facies syndrome, X-linked, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: alpha thalassemia-X-linked intellectual disability syndrome

Similar variants

ATRX p.Arg658His Uncertain significance ★ ⚠ same residue
ATRX p.Arg658Cys Likely benign ★ 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

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-arg658 (accessed [today's date]).

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