Is ATRX p.Asp1349Val (c.4046A>T) pathogenic?

ATRX p.Asp1349Val (c.4046A>T) is classified Uncertain significance in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.7633); Very rare (popmax 0.000894%, nfe); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Asp1349Val (c.4046A>T)?

ATRX p.Asp1349Val (c.4046A>T) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Asp1349Val (c.4046A>T) in the general population?

ATRX p.Asp1349Val (c.4046A>T) is very rare (popmax 0.000894%, nfe) (gnomAD).

What do computational predictors say about ATRX p.Asp1349Val (c.4046A>T)?

AlphaMissense predicts likely pathogenic (score 0.7633) — an in-silico prediction, not a clinical call.

ATRX p.Asp1349Val

c.4046A>T · rs1557124086 · VCV1441245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000894%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alpha thalassemia-X-linked intellectual disability syndrome

Computational evidence

Protein change
AlphaMissense	0.7633	likely pathogenic
REVEL	0.722	pathogenic-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.28 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000894% European (non-Finnish) · 8/895,148 alleles

Filtering AF 0.000384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000729% 8/1,097,689 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.Asp1349Val
Coding: c.4046A>T
MANE Select: NM_000489
dbSNP: rs1557124086
Type: single nucleotide variant
Location: chrX:77663456 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 1349: 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.Asp1349= Likely benign ★★ same residue
ATRX p.Asp1349Gly 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
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-asp1349val (accessed [today's date]).

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