Is ATRX p.Pro449Arg (c.1346C>G) pathogenic?

ATRX p.Pro449Arg (c.1346C>G) is classified Conflicting classifications of pathogenicity in ATRX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.1045); Ultra-rare (popmax 0.0229%, mid); Associated with Inborn genetic diseases.

What condition is associated with ATRX p.Pro449Arg (c.1346C>G)?

ATRX p.Pro449Arg (c.1346C>G) is associated with Inborn genetic diseases, alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Pro449Arg (c.1346C>G) in the general population?

ATRX p.Pro449Arg (c.1346C>G) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about ATRX p.Pro449Arg (c.1346C>G)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

ATRX p.Pro449Arg

c.1346C>G · rs782163488 · VCV588491

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -2.4
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	10.99	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 0.0229% Middle Eastern · 1/4,360 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.0019% 23/1,207,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,360
European (non-Finnish)	0.00235%	42,527
Admixed American	0.00219%	45,721

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.Pro449Arg
Coding: c.1346C>G
MANE Select: NM_000489
dbSNP: rs782163488
Type: single nucleotide variant
Location: chrX:77683910 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 449: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

ATRX p.Pro449Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
ATRX p.Pro449Thr 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-pro449arg (accessed [today's date]).

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