Is ATRX p.Arg2178Trp (c.6532C>T) pathogenic?

ATRX p.Arg2178Trp (c.6532C>T) is classified Pathogenic/Likely pathogenic in ATRX (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-10). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with ATRX p.Arg2178Trp (c.6532C>T)?

ATRX p.Arg2178Trp (c.6532C>T) is associated with intellectual disability-hypotonic facies syndrome, X-linked, 1, alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Arg2178Trp (c.6532C>T) in the general population?

ATRX p.Arg2178Trp (c.6532C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATRX p.Arg2178Trp (c.6532C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

ATRX p.Arg2178Trp

c.6532C>T · rs1057517707 · VCV372309

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9987 · 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	0.9987	likely pathogenic ✓ concordant with ClinVar · top 7% in ATRX
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -16.17	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.10	constrained · MANE · 1,315 bp · p 2.3e-15 · regional, not allelic
Overall
CADD	29.0	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

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.Arg2178Trp
Coding: c.6532C>T
MANE Select: NM_000489
dbSNP: rs1057517707
Type: single nucleotide variant
Location: chrX:77557618 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 2178: the 'interaction with mecp2' region; the helicase c-terminal domain

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.Arg2178= 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
ATRX p.Arg2386Ter 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-arg2178trp (accessed [today's date]).

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