Is TOP3A p.Ser487Arg (c.1459A>C) pathogenic?

TOP3A p.Ser487Arg (c.1459A>C) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-04). AlphaMissense: ambiguous (0.4879); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with TOP3A p.Ser487Arg (c.1459A>C)?

TOP3A p.Ser487Arg (c.1459A>C) is associated with Inborn genetic diseases (ClinVar).

How common is TOP3A p.Ser487Arg (c.1459A>C) in the general population?

TOP3A p.Ser487Arg (c.1459A>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about TOP3A p.Ser487Arg (c.1459A>C)?

AlphaMissense predicts ambiguous (score 0.4879) — an in-silico prediction, not a clinical call.

TOP3A p.Ser487Arg

c.1459A>C · rs1229901127 · VCV2543696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4879	ambiguous
REVEL	0.172	moderately benign-leaning
SaProt	LLR -11.28	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	26.5	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 0.00134% African / African-American · 1/74,898 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,898
European (non-Finnish)	0.000593%	168,571

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.Ser487Arg
Coding: c.1459A>C
MANE Select: NM_004618
dbSNP: rs1229901127
Type: single nucleotide variant
Location: chr17:18290850 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 487: the topo ia-type catalytic domain; 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.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
TOP3A p.Arg722His Uncertain significance ★★ ⚠ same condition
TOP3A p.Arg765Cys 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-ser487arg (accessed [today's date]).

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