Is ATRX p.Thr441Arg (c.1322C>G) pathogenic?

ATRX p.Thr441Arg (c.1322C>G) is classified Uncertain significance in ATRX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1165); Very rare (popmax 0.000671%, nfe); Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with ATRX p.Thr441Arg (c.1322C>G)?

ATRX p.Thr441Arg (c.1322C>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.Thr441Arg (c.1322C>G) in the general population?

ATRX p.Thr441Arg (c.1322C>G) is very rare (popmax 0.000671%, nfe) (gnomAD).

What do computational predictors say about ATRX p.Thr441Arg (c.1322C>G)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

ATRX p.Thr441Arg

c.1322C>G · rs2148625660 · VCV1319036

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000671%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -5.94	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 4.5	GERP 0.95, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	17.77	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000671% European (non-Finnish) · 6/894,292 alleles

Filtering AF 0.000241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000547% 6/1,096,465 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.Thr441Arg
Coding: c.1322C>G
MANE Select: NM_000489
dbSNP: rs2148625660
Type: single nucleotide variant
Location: chrX:77683934 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB

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.Thr441= Likely benign ★ same residue
ATRX p.Thr441Ala Likely benign ★ same residue
ATRX p.Thr441del 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-thr441arg (accessed [today's date]).

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