Is CUL3 p.Leu321Phe (c.963G>C) pathogenic?

CUL3 p.Leu321Phe (c.963G>C) is classified Likely pathogenic in CUL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.9745); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with or without autism or seizures.

What condition is associated with CUL3 p.Leu321Phe (c.963G>C)?

CUL3 p.Leu321Phe (c.963G>C) is associated with neurodevelopmental disorder with or without autism or seizures (ClinVar).

How common is CUL3 p.Leu321Phe (c.963G>C) in the general population?

CUL3 p.Leu321Phe (c.963G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUL3 p.Leu321Phe (c.963G>C)?

AlphaMissense predicts likely pathogenic (score 0.9745) — an in-silico prediction, not a clinical call.

CUL3 p.Leu321Phe

c.963G>C · VCV4526710

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9745 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with or without autism or seizures

Computational evidence

Protein change
AlphaMissense	0.9745	likely pathogenic ✓ concordant with ClinVar
REVEL	0.375	indeterminate
SaProt	LLR -12.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.88	acceptor gain · deltas
Pangolin	Δ0.21	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.8	GERP -0.96, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 76 kb · p 5e-41 · regional, not allelic
Overall
CADD	33.0	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

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.Leu321Phe
Coding: c.963G>C
MANE Select: NM_003590
Type: single nucleotide variant
Location: chr2:224506924 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB
Residue 321: an α-helix

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

Disease context

neurodevelopmental disorder with or without autism or seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUL3 c.883+1G>T Pathogenic ★★ same condition
CUL3 p.Arg128Cys Pathogenic/Likely pathogenic ★★ same condition
CUL3 p.Arg148Ter Pathogenic ★★ same condition
CUL3 p.Arg247Ter Pathogenic ★★ same condition
CUL3 p.Gln641Ter Pathogenic ★★ same condition
CUL3 p.Gly143Ter Likely pathogenic ★★ same condition
CUL3 c.1377+6G>T Uncertain significance ★★ same condition
CUL3 c.884-5T>A 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/cul3-p-leu321phe (accessed [today's date]).

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