Is TOP3A p.Pro727Arg (c.2180C>G) pathogenic?

TOP3A p.Pro727Arg (c.2180C>G) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.2504); Very rare (popmax 8.83e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TOP3A p.Pro727Arg (c.2180C>G)?

TOP3A p.Pro727Arg (c.2180C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TOP3A p.Pro727Arg (c.2180C>G) in the general population?

TOP3A p.Pro727Arg (c.2180C>G) is very rare (popmax 8.83e-05%, nfe) (gnomAD).

What do computational predictors say about TOP3A p.Pro727Arg (c.2180C>G)?

AlphaMissense predicts likely benign (score 0.2504) — an in-silico prediction, not a clinical call.

TOP3A p.Pro727Arg

c.2180C>G · VCV4633418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.83e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2504	likely benign
REVEL	0.536	indeterminate
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.83e-05% European (non-Finnish) · 1/1,132,458 alleles

Overall 0.000657% 1/152,186 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: TOP3A
Protein: p.Pro727Arg
Coding: c.2180C>G
MANE Select: NM_004618
Type: single nucleotide variant
Location: chr17:18278322 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 727: a UniProt-annotated variant site (in peob5)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TOP3A p.Pro727Leu Uncertain significance ★★ ⚠ same residue
TOP3A p.Pro727= Likely benign ★ same residue
TOP3A p.Arg338Ter Pathogenic/Likely pathogenic ★★ same condition
TOP3A p.Ala622Thr Uncertain significance ★★ ⚠ same condition
TOP3A p.Ala642Val Uncertain significance ★★ ⚠ same condition
TOP3A p.Ala941Thr Uncertain significance ★★ ⚠ same condition
TOP3A p.Arg341Lys Uncertain significance ★★ ⚠ same condition
TOP3A p.Arg399Trp 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/top3a-p-pro727arg (accessed [today's date]).

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