Is ATRX p.Ala462= (c.1386T>C) pathogenic?

ATRX p.Ala462= (c.1386T>C) is classified Conflicting classifications of pathogenicity in ATRX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-13). Very rare (popmax 0.00873%, afr); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Ala462= (c.1386T>C)?

ATRX p.Ala462= (c.1386T>C) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Ala462= (c.1386T>C) in the general population?

ATRX p.Ala462= (c.1386T>C) is very rare (popmax 0.00873%, afr) (gnomAD).

ATRX p.Ala462=

c.1386T>C · rs367596462 · VCV210493

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 0.00873%, 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 1.8	GERP -0.06, phastCons 0.47
Overall
CADD	7.138	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00873% African / African-American · 5/57,253 alleles

Filtering AF 0.00338% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00215%

Overall 0.000662% 8/1,208,019 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00873%	11,451
Remaining individualsnot grpmax-eligible	0.00631%	15,849

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.Ala462=
Coding: c.1386T>C
MANE Select: NM_000489
dbSNP: rs367596462
Type: single nucleotide variant
Location: chrX:77683870 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 462: the 'disordered' 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 p.Ala462Pro Benign ★ same residue
ATRX p.Ala462Val Likely benign ★ same residue
ATRX p.Ala462Ser 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
ATRX p.Arg2085His 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-ala462 (accessed [today's date]).

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