Is TOPORS p.Lys894Thr (c.2681A>C) pathogenic?

TOPORS p.Lys894Thr (c.2681A>C) is classified Uncertain significance in TOPORS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-19). AlphaMissense: ambiguous (0.4316); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with TOPORS p.Lys894Thr (c.2681A>C)?

TOPORS p.Lys894Thr (c.2681A>C) is associated with Inborn genetic diseases (ClinVar).

How common is TOPORS p.Lys894Thr (c.2681A>C) in the general population?

TOPORS p.Lys894Thr (c.2681A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TOPORS p.Lys894Thr (c.2681A>C)?

AlphaMissense predicts ambiguous (score 0.4316) — an in-silico prediction, not a clinical call.

TOPORS p.Lys894Thr

c.2681A>C · rs776112643 · VCV850827

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4316	ambiguous
REVEL	0.07	moderately benign-leaning
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 1,627 bp · p 0.22 · regional, not allelic
Overall
CADD	21.4	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 0.00133% African / African-American · 1/74,920 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,048 alleles · very rare exomes 4/1,461,840 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,920
European (non-Finnish)	0.000508%	196,673

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.Lys894Thr
Coding: c.2681A>C
MANE Select: NM_005802
dbSNP: rs776112643
Type: single nucleotide variant
Location: chr9:32541844 (GRCh38)
Gene constraint: LOEUF 0.418 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.39
Residue 894: the 'disordered' region; the 'interaction with ube2i' region

Full TOPORS 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

TOPORS p.Lys894Asn Uncertain significance ★ ⚠ same residue
TOPORS p.Ala154Ser Uncertain significance ★★ ⚠ same condition
TOPORS p.Ala56Ser Uncertain significance ★★ ⚠ same condition
TOPORS p.Ala56Val Uncertain significance ★★ ⚠ same condition
TOPORS p.Ala728Pro Uncertain significance ★★ ⚠ same condition
TOPORS p.Ala901Pro Uncertain significance ★★ ⚠ same condition
TOPORS p.Arg176Gly Uncertain significance ★★ ⚠ same condition
TOPORS p.Arg179Cys 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/topors-p-lys894thr (accessed [today's date]).

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