Is TOP3A p.Arg968Pro (c.2903G>C) pathogenic?

TOP3A p.Arg968Pro (c.2903G>C) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1145); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with TOP3A p.Arg968Pro (c.2903G>C)?

TOP3A p.Arg968Pro (c.2903G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TOP3A p.Arg968Pro (c.2903G>C) in the general population?

TOP3A p.Arg968Pro (c.2903G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TOP3A p.Arg968Pro (c.2903G>C)?

AlphaMissense predicts likely benign (score 0.1145) — an in-silico prediction, not a clinical call.

TOP3A p.Arg968Pro

c.2903G>C · VCV4189062

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1145	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.43, phastCons 0.57
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	14.57	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 0.00223% East Asian · 1/44,884 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very rare

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.Arg968Pro
Coding: c.2903G>C
MANE Select: NM_004618
Type: single nucleotide variant
Location: chr17:18274905 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 968: a UniProt-annotated variant site (in peob5); the 'disordered' region

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.Arg968Gln Uncertain significance ★ ⚠ same residue
TOP3A p.Arg968Trp Uncertain significance ★ ⚠ same residue
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

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-arg968pro (accessed [today's date]).

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