Is TOP3A p.Pro757fs (c.2269_2323del) pathogenic?

TOP3A p.Pro757fs (c.22692323del) is classified Pathogenic in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). Very rare (popmax 8.48e-05%, nfe).

How common is TOP3A p.Pro757fs (c.2269_2323del) in the general population?

TOP3A p.Pro757fs (c.2269_2323del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

TOP3A p.Pro757fs

c.2269_2323del · VCV4716914

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,866 alleles

Overall 6.2e-05% 1/1,613,892 alleles · very rare exomes 1/1,461,676 · genomes 0/152,216 · 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: TOP3A
Protein: p.Pro757fs
Coding: c.2269_2323del
MANE Select: NM_004618
Type: Deletion
Location: chr17:18278179 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 757: a UniProt-annotated variant site (in peob5)

Full TOP3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TOP3A p.Pro757Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TOP3A c.644-11_644-2del Likely pathogenic ★ same type
TOP3A p.Asn343fs Likely pathogenic ★ same type
TOP3A p.Asp386fs Likely pathogenic ★ same type
TOP3A p.Gln450fs Pathogenic ★ same type
TOP3A p.Gln834fs Pathogenic ★ same type
TOP3A p.Ile266fs Pathogenic ★ same type
TOP3A p.Leu374fs 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/top3a-p-pro757fs (accessed [today's date]).

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