Is ATRX p.Val348Leu (c.1042G>T) pathogenic?

ATRX p.Val348Leu (c.1042G>T) is classified Benign in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely benign (0.2807); Very rare (popmax 0.00123%, nfe); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Val348Leu (c.1042G>T)?

ATRX p.Val348Leu (c.1042G>T) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Val348Leu (c.1042G>T) in the general population?

ATRX p.Val348Leu (c.1042G>T) is very rare (popmax 0.00123%, nfe) (gnomAD).

What do computational predictors say about ATRX p.Val348Leu (c.1042G>T)?

AlphaMissense predicts likely benign (score 0.2807) — an in-silico prediction, not a clinical call.

ATRX p.Val348Leu

c.1042G>T · rs1557142408 · VCV842513

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

alpha thalassemia-X-linked intellectual disability syndrome

Computational evidence

Protein change
AlphaMissense	0.2807	likely benign
REVEL	0.457	indeterminate
SaProt	LLR -5.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	22.4	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 0.00123% European (non-Finnish) · 11/895,115 alleles

Filtering AF 0.000659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.000909% 11/1,209,585 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.Val348Leu
Coding: c.1042G>T
MANE Select: NM_000489
dbSNP: rs1557142408
Type: single nucleotide variant
Location: chrX:77684214 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB

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.Val348Ala Uncertain significance ★★ ⚠ same residue
ATRX p.Val348= 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-val348leu (accessed [today's date]).

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