Is TOP2B p.Ser210Arg (c.628A>C) pathogenic?

TOP2B p.Ser210Arg (c.628A>C) is classified Uncertain significance in TOP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely pathogenic (0.6862); Absent from gnomAD v4.1.

How common is TOP2B p.Ser210Arg (c.628A>C) in the general population?

TOP2B p.Ser210Arg (c.628A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOP2B p.Ser210Arg (c.628A>C)?

AlphaMissense predicts likely pathogenic (score 0.6862) — an in-silico prediction, not a clinical call.

TOP2B p.Ser210Arg

c.628A>C · VCV4189038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6862 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6862	likely pathogenic
REVEL	0.137	moderately benign-leaning
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 7,273 bp · p 1.4e-06 · regional, not allelic
Overall
CADD	23.8	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.Ser210Arg
Coding: c.628A>C
MANE Select: NM_001330700
Type: single nucleotide variant
Location: chr3:25637226 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 21 PDB
Residue 210: a β-strand

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

Similar variants

TOP2B p.Ser210Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
TOP2B p.Ala1290Thr Uncertain significance ★★ ⚠ same type
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

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-ser210arg (accessed [today's date]).

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