Is ATRX p.Pro609Ser (c.1825C>T) pathogenic?

ATRX p.Pro609Ser (c.1825C>T) is classified Uncertain significance in ATRX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.0663); Very rare (popmax 0.00176%, sas).

How common is ATRX p.Pro609Ser (c.1825C>T) in the general population?

ATRX p.Pro609Ser (c.1825C>T) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about ATRX p.Pro609Ser (c.1825C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

ATRX p.Pro609Ser

c.1825C>T · rs186742436 · VCV2439410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -4.79	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 1.1	GERP -1.6, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,828 bp · p 3.3e-15 · regional, not allelic
Overall
CADD	12.72	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 · 1/56,940 alleles

Overall 8.27e-05% 1/1,209,534 alleles · very rare exomes 1/1,095,998 · genomes 0/113,536 · joint denominator

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.Pro609Ser
Coding: c.1825C>T
MANE Select: NM_000489
dbSNP: rs186742436
Type: single nucleotide variant
Location: chrX:77683431 (GRCh38)
Structure: AlphaFold pLDDT 52.40 · 13 PDB
Residue 609: the 'disordered' region

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

Similar variants

ATRX p.Pro609Ala Benign ★★ same residue
ATRX p.Pro609= Likely benign ★ same residue
ATRX c.134-2A>G Pathogenic/Likely pathogenic ★★ same type
ATRX c.5449-7A>G Likely pathogenic ★★ same type
ATRX p.Arg1022Ter Pathogenic/Likely pathogenic ★★ same type
ATRX p.Arg1661Cys Likely pathogenic ★★ ⚠ same type
ATRX p.Arg2085Cys Pathogenic/Likely pathogenic ★★ same type
ATRX p.Arg2085His Pathogenic/Likely pathogenic ★★ same type

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-pro609ser (accessed [today's date]).

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