Is TOPORS p.Ser534Phe (c.1601C>T) pathogenic?

TOPORS p.Ser534Phe (c.1601C>T) is classified Uncertain significance in TOPORS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). AlphaMissense: likely benign (0.1247); Very rare (popmax 0.000254%, nfe).

How common is TOPORS p.Ser534Phe (c.1601C>T) in the general population?

TOPORS p.Ser534Phe (c.1601C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TOPORS p.Ser534Phe (c.1601C>T)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

TOPORS p.Ser534Phe

c.1601C>T · rs987806775 · VCV939190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,627 bp · p 0.22 · regional, not allelic
Overall
CADD	23.7	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 0.000254% European (non-Finnish) · 3/1,180,020 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,008 alleles · very rare exomes 2/1,461,848 · genomes 1/152,160 · joint denominator

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: TOPORS
Protein: p.Ser534Phe
Coding: c.1601C>T
MANE Select: NM_005802
dbSNP: rs987806775
Type: single nucleotide variant
Location: chr9:32542924 (GRCh38)
Gene constraint: LOEUF 0.418 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.39
Residue 534: the 'disordered' region; 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.Ser534Pro Uncertain significance ★ ⚠ same residue
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

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-ser534phe (accessed [today's date]).

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