Is TOP3A p.Arg323= (c.967C>A) pathogenic?

TOP3A p.Arg323= (c.967C>A) is classified Likely benign in TOP3A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-29). Ultra-rare (popmax 0.033%, mid); Associated with TOP3A-related disorder.

What condition is associated with TOP3A p.Arg323= (c.967C>A)?

TOP3A p.Arg323= (c.967C>A) is associated with TOP3A-related disorder (ClinVar).

How common is TOP3A p.Arg323= (c.967C>A) in the general population?

TOP3A p.Arg323= (c.967C>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

TOP3A p.Arg323=

c.967C>A · rs138933272 · VCV3055276

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

TOP3A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.186	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.5	GERP -1.8, phastCons 1
Overall
CADD	7.587	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00136% 22/1,614,016 alleles · ultra-rare exomes 18/1,461,740 · genomes 4/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.0253%	3,948
South Asian	0.0011%	91,076

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.Arg323=
Coding: c.967C>A
MANE Select: NM_004618
dbSNP: rs138933272
Type: single nucleotide variant
Location: chr17:18299582 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 323: the topo ia-type catalytic domain; a UniProt-annotated variant site (in peob5); an α-helix

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

Disease context

TOP3A-related disorder

Similar variants

TOP3A p.Arg135Ter Pathogenic/Likely pathogenic ★★ same condition
TOP3A p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
TOP3A c.990+1G>A Pathogenic ★ same condition
TOP3A p.Leu302Ter Likely pathogenic ★ same condition
TOP3A p.Arg585Gln Uncertain significance ★ ⚠ same condition
TOP3A p.Arg968Trp Uncertain significance ★ ⚠ same condition
TOP3A p.Thr504= Likely benign same condition
TOP3A p.Asn343fs Likely pathogenic ★ 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-arg323 (accessed [today's date]).

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