Is TOPORS p.Pro486Ser (c.1456C>T) pathogenic?

TOPORS p.Pro486Ser (c.1456C>T) is classified Uncertain significance in TOPORS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely pathogenic (0.9837); Absent from gnomAD v4.1.

How common is TOPORS p.Pro486Ser (c.1456C>T) in the general population?

TOPORS p.Pro486Ser (c.1456C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOPORS p.Pro486Ser (c.1456C>T)?

AlphaMissense predicts likely pathogenic (score 0.9837) — an in-silico prediction, not a clinical call.

TOPORS p.Pro486Ser

c.1456C>T · rs766614573 · VCV2055425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9837 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9837	likely pathogenic · top 8% in TOPORS
REVEL	0.483	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 97 bp · p 0.00018 · regional, not allelic
Overall
CADD	24.0	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

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: TOPORS
Protein: p.Pro486Ser
Coding: c.1456C>T
MANE Select: NM_005802
dbSNP: rs766614573
Type: single nucleotide variant
Location: chr9:32543069 (GRCh38)
Gene constraint: LOEUF 0.418 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.39
Residue 486: the 'interaction with sumo1' region; the 'required for sumoylation and localization to discrete nuclear foci' region; the 'interaction with top1' region; the 'interaction with p53/tp53' region

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

Similar variants

TOPORS p.Arg847Ter Pathogenic/Likely pathogenic ★★ same type
TOPORS p.Gln811Ter Likely pathogenic ★★ same type
TOPORS p.Glu808Ter Pathogenic ★★ same type
TOPORS c.*300A>G Uncertain significance ★★ same type
TOPORS p.Ala154Ser Uncertain significance ★★ ⚠ same type
TOPORS p.Ala190Thr Uncertain significance ★★ ⚠ same type
TOPORS p.Ala399Asp Uncertain significance ★★ ⚠ same type
TOPORS p.Ala56Ser 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/topors-p-pro486ser (accessed [today's date]).

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