Is ATRX p.Pro2218Leu (c.6653C>T) pathogenic?

ATRX p.Pro2218Leu (c.6653C>T) is classified Uncertain significance in ATRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-06). AlphaMissense: likely pathogenic (0.6571); Very rare (popmax 0.00176%, sas); Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with ATRX p.Pro2218Leu (c.6653C>T)?

ATRX p.Pro2218Leu (c.6653C>T) is associated with intellectual disability-hypotonic facies syndrome, X-linked, 1 (ClinVar).

How common is ATRX p.Pro2218Leu (c.6653C>T) in the general population?

ATRX p.Pro2218Leu (c.6653C>T) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about ATRX p.Pro2218Leu (c.6653C>T)?

AlphaMissense predicts likely pathogenic (score 0.6571) — an in-silico prediction, not a clinical call.

ATRX p.Pro2218Leu

c.6653C>T · rs2147941337 · VCV1333729

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6571	likely pathogenic
REVEL	0.592	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 35 kb · p 2e-06 · regional, not allelic
Overall
CADD	24.7	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 0.00176% South Asian · 1/56,881 alleles

Overall 9.11e-05% 1/1,097,245 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.Pro2218Leu
Coding: c.6653C>T
MANE Select: NM_000489
dbSNP: rs2147941337
Type: single nucleotide variant
Location: chrX:77557497 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 2218: the 'interaction with mecp2' region

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 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
ATRX p.Arg2386Ter Pathogenic ★★ same condition
ATRX p.Arg246Cys Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg37Ter Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Asn179Ser 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-pro2218leu (accessed [today's date]).

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