Is CUL3 p.Ser450Phe (c.1349C>T) pathogenic?

CUL3 p.Ser450Phe (c.1349C>T) is classified Likely pathogenic in CUL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely pathogenic (0.7929); Absent from gnomAD v4.1; Associated with CUL3-related disorder.

What condition is associated with CUL3 p.Ser450Phe (c.1349C>T)?

CUL3 p.Ser450Phe (c.1349C>T) is associated with CUL3-related disorder (ClinVar).

How common is CUL3 p.Ser450Phe (c.1349C>T) in the general population?

CUL3 p.Ser450Phe (c.1349C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUL3 p.Ser450Phe (c.1349C>T)?

AlphaMissense predicts likely pathogenic (score 0.7929) — an in-silico prediction, not a clinical call.

CUL3 p.Ser450Phe

c.1349C>T · rs2106196630 · VCV2636475

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7929 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CUL3-related disorder

Computational evidence

Protein change
AlphaMissense	0.7929	likely pathogenic ✓ concordant with ClinVar
REVEL	0.39	indeterminate
SaProt	LLR -10.59	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 76 kb · p 5e-41 · regional, not allelic
Overall
CADD	24.1	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.Ser450Phe
Coding: c.1349C>T
MANE Select: NM_003590
dbSNP: rs2106196630
Type: single nucleotide variant
Location: chr2:224503680 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.68 · 31 PDB

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

Disease context

CUL3-related disorder

Similar variants

CUL3 c.1377+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUL3 p.Arg438Gly Pathogenic ★★ same condition
CUL3 c.1207-12T>A Likely pathogenic ★ same condition
CUL3 p.Asp413Gly Likely pathogenic ★ same condition
CUL3 p.Cys187Tyr Likely pathogenic ★ same condition
CUL3 p.Ser450fs Pathogenic ★ same residue
CUL3 c.67-11915T>C Uncertain significance ★ same condition
CUL3 p.Arg430His 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-ser450phe (accessed [today's date]).

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