Is ATRX p.Ser338Pro (c.1012T>C) pathogenic?

ATRX p.Ser338Pro (c.1012T>C) is classified Likely benign in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-21). AlphaMissense: likely benign (0.1418); Absent from gnomAD v4.1; Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with ATRX p.Ser338Pro (c.1012T>C)?

ATRX p.Ser338Pro (c.1012T>C) is associated with intellectual disability-hypotonic facies syndrome, X-linked, 1 (ClinVar).

How common is ATRX p.Ser338Pro (c.1012T>C) in the general population?

ATRX p.Ser338Pro (c.1012T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATRX p.Ser338Pro (c.1012T>C)?

AlphaMissense predicts likely benign (score 0.1418) — an in-silico prediction, not a clinical call.

ATRX p.Ser338Pro

c.1012T>C · VCV4796742

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1418 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1418	likely benign
REVEL	0.42	indeterminate
SaProt	LLR -7.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	21.0	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.Ser338Pro
Coding: c.1012T>C
MANE Select: NM_000489
Type: single nucleotide variant
Location: chrX:77684244 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB

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.Ser338Cys 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
ATRX p.Arg2386Ter Pathogenic ★★ same condition
ATRX p.Arg246Cys Pathogenic/Likely pathogenic ★★ same condition
ATRX p.Arg37Ter 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-ser338pro (accessed [today's date]).

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