Is TOP2A p.Phe968Ser (c.2903T>C) pathogenic?

TOP2A p.Phe968Ser (c.2903T>C) is classified Uncertain significance in TOP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1.

How common is TOP2A p.Phe968Ser (c.2903T>C) in the general population?

TOP2A p.Phe968Ser (c.2903T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOP2A p.Phe968Ser (c.2903T>C)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

TOP2A p.Phe968Ser

c.2903T>C · VCV4189028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic · top 9% in TOP2A
REVEL	0.574	indeterminate
SaProt	LLR -16.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 2,063 bp · p 2.3e-05 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: TOP2A
Protein: p.Phe968Ser
Coding: c.2903T>C
MANE Select: NM_001067
Type: single nucleotide variant
Location: chr17:40400306 (GRCh38)
Gene constraint: LOEUF 0.422 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.33 · 15 PDB
Residue 968: the topo iia-type catalytic domain; a β-strand

Full TOP2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TOP2A p.Pro1194Arg Uncertain significance ★★ ⚠ same type
TOP2A p.Ala243= Benign ★★ same type
TOP2A p.Asn774Ile Likely benign ★★ same type
TOP2A p.Glu571= Benign ★★ same type
TOP2A p.Gly1197Ala Likely benign ★★ same type
TOP2A p.Gly1197Glu Likely benign ★★ same type
TOP2A p.Lys976= Benign ★★ same type
TOP2A p.Pro643= Likely benign ★★ 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/top2a-p-phe968ser (accessed [today's date]).

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