Is ATRX p.Ala462Pro (c.1384G>C) pathogenic?

ATRX p.Ala462Pro (c.1384G>C) is classified Benign in ATRX (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1187); Very rare (popmax 0.000224%, nfe); Associated with alpha thalassemia-X-linked intellectual disability syndrome.

What condition is associated with ATRX p.Ala462Pro (c.1384G>C)?

ATRX p.Ala462Pro (c.1384G>C) is associated with alpha thalassemia-X-linked intellectual disability syndrome (ClinVar).

How common is ATRX p.Ala462Pro (c.1384G>C) in the general population?

ATRX p.Ala462Pro (c.1384G>C) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about ATRX p.Ala462Pro (c.1384G>C)?

AlphaMissense predicts likely benign (score 0.1187) — an in-silico prediction, not a clinical call.

ATRX p.Ala462Pro

c.1384G>C · rs201503118 · VCV1169376

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alpha thalassemia-X-linked intellectual disability syndrome

Computational evidence

Protein change
AlphaMissense	0.1187	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -6.50	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 0.54	GERP 0.83, phastCons 0.12
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	13.54	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 0.000224% European (non-Finnish) · 2/893,810 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000274% 3/1,095,975 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,592
European (non-Finnish)grpmax	0.000224%	446,905

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala462Pro
Coding: c.1384G>C
MANE Select: NM_000489
dbSNP: rs201503118
Type: single nucleotide variant
Location: chrX:77683872 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 462: the 'disordered' region

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.Ala462= Conflicting classifications of pathogenicity ★ same residue
ATRX p.Ala462Val Likely benign ★ same residue
ATRX p.Ala462Ser 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-ala462pro (accessed [today's date]).

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