Is TOPORS p.Pro44Leu (c.131C>T) pathogenic?

TOPORS p.Pro44Leu (c.131C>T) is classified Uncertain significance in TOPORS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.2095); Absent from gnomAD v4.1.

How common is TOPORS p.Pro44Leu (c.131C>T) in the general population?

TOPORS p.Pro44Leu (c.131C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOPORS p.Pro44Leu (c.131C>T)?

AlphaMissense predicts likely benign (score 0.2095) — an in-silico prediction, not a clinical call.

TOPORS p.Pro44Leu

c.131C>T · rs952765710 · VCV2119563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2095 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2095	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 8,116 bp · p 0.0029 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: TOPORS
Protein: p.Pro44Leu
Coding: c.131C>T
MANE Select: NM_005802
dbSNP: rs952765710
Type: single nucleotide variant
Location: chr9:32550841 (GRCh38)
Gene constraint: LOEUF 0.418 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.39
Residue 44: the 'e3 ubiquitin-protein ligase activity' region

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

Similar variants

TOPORS p.Pro44= Likely benign ★ 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-pro44leu (accessed [today's date]).

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