Is TOPORS p.Lys892Gln (c.2674A>C) pathogenic?

TOPORS p.Lys892Gln (c.2674A>C) is classified Uncertain significance in TOPORS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-21). AlphaMissense: ambiguous (0.472); Very rare (popmax 0.000508%, nfe); Associated with retinitis pigmentosa 31.

What condition is associated with TOPORS p.Lys892Gln (c.2674A>C)?

TOPORS p.Lys892Gln (c.2674A>C) is associated with retinitis pigmentosa 31 (ClinVar).

How common is TOPORS p.Lys892Gln (c.2674A>C) in the general population?

TOPORS p.Lys892Gln (c.2674A>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TOPORS p.Lys892Gln (c.2674A>C)?

AlphaMissense predicts ambiguous (score 0.472) — an in-silico prediction, not a clinical call.

TOPORS p.Lys892Gln

c.2674A>C · VCV3597250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

retinitis pigmentosa 31

Computational evidence

Protein change
AlphaMissense	0.472	ambiguous
REVEL	0.093	moderately benign-leaning
SaProt	LLR -10.94	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 6	GERP 2.2, 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 0.000508% European (non-Finnish) · 6/1,179,984 alleles

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

Overall 0.000372% 6/1,614,116 alleles · very rare exomes 6/1,461,792 · genomes 0/152,324 · 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.Lys892Gln
Coding: c.2674A>C
MANE Select: NM_005802
Type: single nucleotide variant
Location: chr9:32541851 (GRCh38)
Gene constraint: LOEUF 0.418 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.39
Residue 892: the 'disordered' region; the 'interaction with ube2i' region

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

Disease context

retinitis pigmentosa 31 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

TOPORS p.Lys892Arg Likely benign ★ same residue
TOPORS p.Arg847Ter Pathogenic/Likely pathogenic ★★ same condition
TOPORS p.Arg851Lys Uncertain significance ★★ ⚠ same condition
TOPORS p.His889Arg Uncertain significance ★★ ⚠ same condition
TOPORS p.Leu865Pro Uncertain significance ★★ ⚠ same condition
TOPORS p.Gly783= Benign/Likely benign ★★ same condition
TOPORS p.Leu996= Benign/Likely benign ★★ same condition
TOPORS p.Ser25Trp Benign/Likely benign ★★ 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-lys892gln (accessed [today's date]).

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