Is TOP2B p.Ala19Pro (c.55G>C) pathogenic?

TOP2B p.Ala19Pro (c.55G>C) is classified Conflicting classifications of pathogenicity in TOP2B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-08). AlphaMissense: likely benign (0.1553); Ultra-rare (popmax 0.0639%, eas).

How common is TOP2B p.Ala19Pro (c.55G>C) in the general population?

TOP2B p.Ala19Pro (c.55G>C) is ultra-rare (popmax 0.0639%, eas) (gnomAD).

What do computational predictors say about TOP2B p.Ala19Pro (c.55G>C)?

AlphaMissense predicts likely benign (score 0.1553) — an in-silico prediction, not a clinical call.

TOP2B p.Ala19Pro

c.55G>C · rs777837072 · VCV1566562

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1553 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0639%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1553	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -6.43	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 4	GERP 0.41, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 19 kb · p 0.0021 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 0.0639% East Asian · 26/40,714 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00221% 34/1,538,678 alleles · ultra-rare exomes 27/1,386,554 · genomes 7/152,124 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0639%	1,566
Remaining individualsnot grpmax-eligible	0.0117%	8,551
Admixed American	0.00196%	50,912

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.Ala19Pro
Coding: c.55G>C
MANE Select: NM_001330700
dbSNP: rs777837072
Type: single nucleotide variant
Location: chr3:25664243 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 21 PDB

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

Similar variants

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
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-ala19pro (accessed [today's date]).

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