Is TOP3A p.Pro385Ser (c.1153C>T) pathogenic?

TOP3A p.Pro385Ser (c.1153C>T) is classified Uncertain significance in TOP3A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-04). AlphaMissense: likely benign (0.0558); Ultra-rare (popmax 0.0152%, nfe).

How common is TOP3A p.Pro385Ser (c.1153C>T) in the general population?

TOP3A p.Pro385Ser (c.1153C>T) is ultra-rare (popmax 0.0152%, nfe) (gnomAD).

What do computational predictors say about TOP3A p.Pro385Ser (c.1153C>T)?

AlphaMissense predicts likely benign (score 0.0558) — an in-silico prediction, not a clinical call.

TOP3A p.Pro385Ser

c.1153C>T · rs139068958 · VCV1386364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0558	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -5.82	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 0.21	GERP -2
Regional constraint	o/e 0.86	unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	15.23	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 0.0152% European (non-Finnish) · 179/1,179,992 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0126%

Overall 0.0114% 184/1,613,966 alleles · ultra-rare exomes 174/1,461,780 · genomes 10/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0152%	6,592
African / African-American	0.004%	24,976
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Pro385Ser
Coding: c.1153C>T
MANE Select: NM_004618
dbSNP: rs139068958
Type: single nucleotide variant
Location: chr17:18292773 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 2 PDB
Residue 385: the topo ia-type catalytic domain; a UniProt-annotated variant site (in peob5); a turn

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

Similar variants

TOP3A p.Pro385= Likely benign ★ same residue
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

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-pro385ser (accessed [today's date]).

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