Is TOP3A p.Ala796Pro (c.2386G>C) pathogenic?

TOP3A p.Ala796Pro (c.2386G>C) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0747%, sas).

How common is TOP3A p.Ala796Pro (c.2386G>C) in the general population?

TOP3A p.Ala796Pro (c.2386G>C) is ultra-rare (popmax 0.0747%, sas) (gnomAD).

What do computational predictors say about TOP3A p.Ala796Pro (c.2386G>C)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

TOP3A p.Ala796Pro

c.2386G>C · rs572424841 · VCV1918984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.4	GERP -3.4
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	0.279	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 0.0747% South Asian · 68/91,088 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0551%

Overall 0.00446% 72/1,614,210 alleles · ultra-rare exomes 68/1,461,880 · genomes 4/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0747%	1,340
Remaining individualsnot grpmax-eligible	0.0064%	15,627

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.Ala796Pro
Coding: c.2386G>C
MANE Select: NM_004618
dbSNP: rs572424841
Type: single nucleotide variant
Location: chr17:18278116 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 796: a UniProt-annotated variant site (in peob5); the 'disordered' region

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

Similar variants

TOP3A c.990+1G>T Likely pathogenic ★★ same type
TOP3A p.Arg135Ter Pathogenic/Likely pathogenic ★★ same type
TOP3A p.Arg177Ter Pathogenic/Likely pathogenic ★★ same type
TOP3A p.Arg338Ter Pathogenic/Likely pathogenic ★★ same type
TOP3A p.Ala622Thr Uncertain significance ★★ ⚠ same type
TOP3A p.Ala642Val Uncertain significance ★★ ⚠ same type
TOP3A p.Ala941Thr Uncertain significance ★★ ⚠ same type
TOP3A p.Arg341Lys 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/top3a-p-ala796pro (accessed [today's date]).

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