Is ATRX p.Arg246His (c.737G>A) pathogenic?

ATRX p.Arg246His (c.737G>A) is classified Uncertain significance in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9792); Absent from gnomAD v4.1; Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with ATRX p.Arg246His (c.737G>A)?

ATRX p.Arg246His (c.737G>A) is associated with intellectual disability-hypotonic facies syndrome, X-linked, 1 (ClinVar).

How common is ATRX p.Arg246His (c.737G>A) in the general population?

ATRX p.Arg246His (c.737G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATRX p.Arg246His (c.737G>A)?

AlphaMissense predicts likely pathogenic (score 0.9792) — an in-silico prediction, not a clinical call.

ATRX p.Arg246His

c.737G>A · VCV4293812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9792 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9792	likely pathogenic
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -12.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 4,427 bp · p 3.6e-13 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATRX
Protein: p.Arg246His
Coding: c.737G>A
MANE Select: NM_000489
Type: single nucleotide variant
Location: chrX:77684519 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 246: the add domain; a UniProt-annotated variant site (in atrx; impairs interaction with histone h3 peptides trimethylated at 'lys-10' (h3k9me3) and reduces localization to pericentromeric heterochromatin foci); a UniProt-annotated variant site (in atrx; impairs interaction with histone h3 peptides trimethylated at 'lys-10' (h3k9me3)); an α-helix

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

Similar variants

ATRX p.Arg246Cys Pathogenic/Likely pathogenic ★★ same residue
ATRX p.Arg246= Likely benign ★★ same residue
ATRX p.Arg246Gly Likely pathogenic ★ same residue
ATRX p.Arg246Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ATRX c.5449-7A>G Likely pathogenic ★★ same condition
ATRX p.Arg2085His Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg2131Gln Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg2178Trp 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-arg246his (accessed [today's date]).

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