Is CUL9 p.Pro2116Leu (c.6347C>T) pathogenic?

CUL9 p.Pro2116Leu (c.6347C>T) is classified Uncertain significance in CUL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-25). AlphaMissense: likely pathogenic (0.7657); Absent from gnomAD v4.1.

How common is CUL9 p.Pro2116Leu (c.6347C>T) in the general population?

CUL9 p.Pro2116Leu (c.6347C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CUL9 p.Pro2116Leu (c.6347C>T)?

AlphaMissense predicts likely pathogenic (score 0.7657) — an in-silico prediction, not a clinical call.

CUL9 p.Pro2116Leu

c.6347C>T · VCV3498701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7657 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7657	likely pathogenic
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 36 kb · p 3.2e-27 · regional, not allelic
Overall
CADD	27.6	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: CUL9
Protein: p.Pro2116Leu
Coding: c.6347C>T
MANE Select: NM_015089
Type: single nucleotide variant
Location: chr6:43220523 (GRCh38)
Gene constraint: LOEUF 0.334 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.64 · 4 PDB
Residue 2116: the 'triad supradomain' region

Full CUL9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUL9 p.Glu617Lys Likely benign ★★ ⚠ same type
CUL9 c.1987+2T>C Uncertain significance ★ same type
CUL9 p.Ala1004Val Uncertain significance ★ ⚠ same type
CUL9 p.Ala1093Pro Uncertain significance ★ ⚠ same type
CUL9 p.Ala1112Thr Uncertain significance ★ ⚠ same type
CUL9 p.Ala111Thr Uncertain significance ★ ⚠ same type
CUL9 p.Ala121Glu Uncertain significance ★ ⚠ same type
CUL9 p.Ala131Val 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/cul9-p-pro2116leu (accessed [today's date]).

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