Is CUL3 p.Leu722Pro (c.2165T>C) pathogenic?

CUL3 p.Leu722Pro (c.2165T>C) is classified Uncertain significance in CUL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is CUL3 p.Leu722Pro (c.2165T>C) in the general population?

CUL3 p.Leu722Pro (c.2165T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUL3 p.Leu722Pro (c.2165T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

CUL3 p.Leu722Pro

c.2165T>C · VCV3393654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 7% in CUL3
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -17.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 7,716 bp · p 9.8e-12 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: CUL3
Protein: p.Leu722Pro
Coding: c.2165T>C
MANE Select: NM_003590
Type: single nucleotide variant
Location: chr2:224478210 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB
Residue 722: a UniProt-annotated variant site (in nedaus); the cullin neddylation domain

Full CUL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUL3 p.Leu722Val Uncertain significance ★★ ⚠ same residue
CUL3 c.1377+1G>A Pathogenic/Likely pathogenic ★★ same type
CUL3 c.1377+4A>G Likely pathogenic ★★ same type
CUL3 c.883+1G>A Pathogenic/Likely pathogenic ★★ same type
CUL3 c.883+1G>T Pathogenic ★★ same type
CUL3 p.Arg128Cys Pathogenic/Likely pathogenic ★★ same type
CUL3 p.Arg148Ter Pathogenic ★★ same type
CUL3 p.Arg247Ter Pathogenic ★★ 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/cul3-p-leu722pro (accessed [today's date]).

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