Is TOP3A p.Ala620Val (c.1859C>T) pathogenic?

TOP3A p.Ala620Val (c.1859C>T) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-04). AlphaMissense: ambiguous (0.3733); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with TOP3A p.Ala620Val (c.1859C>T)?

TOP3A p.Ala620Val (c.1859C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TOP3A p.Ala620Val (c.1859C>T) in the general population?

TOP3A p.Ala620Val (c.1859C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about TOP3A p.Ala620Val (c.1859C>T)?

AlphaMissense predicts ambiguous (score 0.3733) — an in-silico prediction, not a clinical call.

TOP3A p.Ala620Val

c.1859C>T · VCV4865854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3733	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -10.47	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	25.2	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00103% 15/1,461,702 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.00833%	12,004
East Asian	0.00223%	44,890
European (non-Finnish)	0.000593%	168,572

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.Ala620Val
Coding: c.1859C>T
MANE Select: NM_004618
Type: single nucleotide variant
Location: chr17:18285160 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 620: 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

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-ala620val (accessed [today's date]).

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