Is TOP2B p.Ala490Pro (c.1468G>C) pathogenic?

TOP2B p.Ala490Pro (c.1468G>C) is classified Pathogenic in TOP2B (ClinVar, Single submitter, 2 submitters; last evaluated 2023-11-24). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with TOP2B-related disorder.

What condition is associated with TOP2B p.Ala490Pro (c.1468G>C)?

TOP2B p.Ala490Pro (c.1468G>C) is associated with TOP2B-related disorder, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations (ClinVar).

How common is TOP2B p.Ala490Pro (c.1468G>C) in the general population?

TOP2B p.Ala490Pro (c.1468G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOP2B p.Ala490Pro (c.1468G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

TOP2B p.Ala490Pro

c.1468G>C · rs2125377898 · VCV1319985

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TOP2B-related disorder

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 4% in TOP2B
REVEL	0.694	pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 876 bp · p 1.8e-12 · regional, not allelic
Overall
CADD	26.9	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: TOP2B
Protein: p.Ala490Pro
Coding: c.1468G>C
MANE Select: NM_001330700
dbSNP: rs2125377898
Type: single nucleotide variant
Location: chr3:25630407 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 21 PDB
Residue 490: a UniProt-annotated variant site (in bilu; decreased protein abundance; severely decreased dna topoisomerase type ii (double strand cut, atp-hydrolyzing) activity); an α-helix; the toprim domain

Full TOP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TOP2B-related disorder

Also linked: B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

Similar variants

TOP2B p.Ala490= Likely benign ★★ same residue
TOP2B p.Glu547Gln Uncertain significance ★★ ⚠ same condition
TOP2B p.Ile227Ser Uncertain significance ★★ ⚠ same condition
TOP2B p.Ile623Thr Uncertain significance ★★ ⚠ same condition
TOP2B p.Ile789Thr Uncertain significance ★★ ⚠ same condition
TOP2B p.Met1624Val Uncertain significance ★★ ⚠ same condition
TOP2B p.Thr1317Ile Uncertain significance ★★ ⚠ same condition
TOP2B p.Val1504Phe 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/top2b-p-ala490pro (accessed [today's date]).

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