Is TOP2B p.Ala526Pro (c.1576G>C) pathogenic?

TOP2B p.Ala526Pro (c.1576G>C) is classified Uncertain significance in TOP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-07). AlphaMissense: likely pathogenic (0.9677); Very rare (popmax 0.00241%, sas).

How common is TOP2B p.Ala526Pro (c.1576G>C) in the general population?

TOP2B p.Ala526Pro (c.1576G>C) is very rare (popmax 0.00241%, sas) (gnomAD).

What do computational predictors say about TOP2B p.Ala526Pro (c.1576G>C)?

AlphaMissense predicts likely pathogenic (score 0.9677) — an in-silico prediction, not a clinical call.

TOP2B p.Ala526Pro

c.1576G>C · rs1702914857 · VCV1025593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00241%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9677	likely pathogenic
REVEL	0.551	indeterminate
SaProt	LLR -11.59	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00241% South Asian · 2/82,874 alleles

Filtering AF 0.000401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00015%

Overall 0.000143% 2/1,400,236 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: TOP2B
Protein: p.Ala526Pro
Coding: c.1576G>C
MANE Select: NM_001330700
dbSNP: rs1702914857
Type: single nucleotide variant
Location: chr3:25630142 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 21 PDB
Residue 526: an α-helix; the toprim domain

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

Similar variants

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TOP2B p.Ala188Gly Uncertain significance ★★ ⚠ same type
TOP2B p.Ala777Ser Uncertain significance ★★ ⚠ same type
TOP2B p.Ala890Ser Uncertain significance ★★ ⚠ same type
TOP2B p.Arg1047Gln Uncertain significance ★★ ⚠ same type
TOP2B p.Arg1074Cys Uncertain significance ★★ ⚠ same type
TOP2B p.Arg1171Gln Uncertain significance ★★ ⚠ same type
TOP2B p.Arg1305Thr Uncertain significance ★★ ⚠ 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/top2b-p-ala526pro (accessed [today's date]).

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