Is TOP3A p.Ala45Val (c.134C>T) pathogenic?

TOP3A p.Ala45Val (c.134C>T) is classified Conflicting classifications of pathogenicity in TOP3A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-11). AlphaMissense: likely benign (0.3234); Rare (popmax 0.395%, eas); Associated with Inborn genetic diseases.

What condition is associated with TOP3A p.Ala45Val (c.134C>T)?

TOP3A p.Ala45Val (c.134C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TOP3A p.Ala45Val (c.134C>T) in the general population?

TOP3A p.Ala45Val (c.134C>T) is rare (popmax 0.395%, eas) (gnomAD).

What do computational predictors say about TOP3A p.Ala45Val (c.134C>T)?

AlphaMissense predicts likely benign (score 0.3234) — an in-silico prediction, not a clinical call.

TOP3A p.Ala45Val

c.134C>T · rs559137278 · VCV2164598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3234 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.395%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3234	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -10.94	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.61, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	33.0	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 0.395% East Asian · 177/44,764 alleles

Filtering AF 0.348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.33%

Overall 0.014% 226/1,613,310 alleles · rare exomes 206/1,461,000 · genomes 20/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.395%	253
Remaining individualsnot grpmax-eligible	0.0192%	5,206
South Asian	0.0055%	18,186
European (non-Finnish)	0.00271%	36,864

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.Ala45Val
Coding: c.134C>T
MANE Select: NM_004618
dbSNP: rs559137278
Type: single nucleotide variant
Location: chr17:18314645 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 45: the toprim domain; 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-ala45val (accessed [today's date]).

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