Is ATRX p.Leu409Ser (c.1226T>C) pathogenic?

ATRX p.Leu409Ser (c.1226T>C) is classified Pathogenic in ATRX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2005-02-01). AlphaMissense: likely pathogenic (0.7709); Absent from gnomAD v4.1; Associated with Intellectual disability-hypotonic facies syndrome, X-linked.

What condition is associated with ATRX p.Leu409Ser (c.1226T>C)?

ATRX p.Leu409Ser (c.1226T>C) is associated with Intellectual disability-hypotonic facies syndrome, X-linked (ClinVar).

How common is ATRX p.Leu409Ser (c.1226T>C) in the general population?

ATRX p.Leu409Ser (c.1226T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATRX p.Leu409Ser (c.1226T>C)?

AlphaMissense predicts likely pathogenic (score 0.7709) — an in-silico prediction, not a clinical call.

ATRX p.Leu409Ser

c.1226T>C · rs122445109 · VCV11743

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7709 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability-hypotonic facies syndrome, X-linked

Computational evidence

Protein change
AlphaMissense	0.7709	likely pathogenic ✓ concordant with ClinVar
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	22.6	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.Leu409Ser
Coding: c.1226T>C
MANE Select: NM_000489
dbSNP: rs122445109
Type: single nucleotide variant
Location: chrX:77684030 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 409: a UniProt-annotated variant site (in mrxhf1)

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

Disease context

Intellectual disability-hypotonic facies syndrome, X-linked

Similar variants

ATRX p.Leu409Val Uncertain significance ★ ⚠ same residue
ATRX p.Leu409= Likely benign ★ same residue
ATRX p.Arg2085His Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg2131Gln Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Phe1780Tyr Likely pathogenic ★★ same condition
ATRX p.Cys280Arg Uncertain significance ★★ ⚠ same condition
ATRX p.Ser1067Leu Uncertain significance ★★ ⚠ same condition
ATRX p.Thr2117Ala Uncertain significance ★★ ⚠ 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-leu409ser (accessed [today's date]).

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