Is TOP3A p.Ala622Pro (c.1864G>C) pathogenic?

TOP3A p.Ala622Pro (c.1864G>C) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.6397); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TOP3A p.Ala622Pro (c.1864G>C)?

TOP3A p.Ala622Pro (c.1864G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TOP3A p.Ala622Pro (c.1864G>C) in the general population?

TOP3A p.Ala622Pro (c.1864G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOP3A p.Ala622Pro (c.1864G>C)?

AlphaMissense predicts likely pathogenic (score 0.6397) — an in-silico prediction, not a clinical call.

TOP3A p.Ala622Pro

c.1864G>C · VCV4189059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6397 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6397	likely pathogenic
REVEL	0.07	moderately benign-leaning
SaProt	LLR -11.35	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.58, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	20.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TOP3A
Protein: p.Ala622Pro
Coding: c.1864G>C
MANE Select: NM_004618
Type: single nucleotide variant
Location: chr17:18285155 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 622: 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.Ala622Thr Uncertain significance ★★ ⚠ same residue
TOP3A p.Arg338Ter Pathogenic/Likely pathogenic ★★ 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-ala622pro (accessed [today's date]).

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