Is CUL9 p.Pro1518Ser (c.4552C>T) pathogenic?

CUL9 p.Pro1518Ser (c.4552C>T) is classified Uncertain significance in CUL9 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.098); Rare (popmax 0.328%, afr).

How common is CUL9 p.Pro1518Ser (c.4552C>T) in the general population?

CUL9 p.Pro1518Ser (c.4552C>T) is rare (popmax 0.328%, afr) (gnomAD).

What do computational predictors say about CUL9 p.Pro1518Ser (c.4552C>T)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

CUL9 p.Pro1518Ser

c.4552C>T · rs146237222 · VCV3035887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.328%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -5.93	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 1.8	GERP -1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 36 kb · p 3.2e-27 · regional, not allelic
Overall
CADD	16.97	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

Grpmax group 0.328% African / African-American · 246/75,038 alleles

Filtering AF 0.294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.281%

Overall 0.0223% 360/1,612,692 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.328%	305
Admixed American	0.0901%	1,110
Remaining individualsnot grpmax-eligible	0.0416%	2,403
South Asian	0.033%	3,033
European (non-Finnish)	0.000339%	294,883

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CUL9
Protein: p.Pro1518Ser
Coding: c.4552C>T
MANE Select: NM_015089
dbSNP: rs146237222
Type: single nucleotide variant
Location: chr6:43205035 (GRCh38)
Gene constraint: LOEUF 0.334 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.64 · 4 PDB

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-pro1518ser (accessed [today's date]).

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