Is CUL9 p.Arg1307Trp (c.3919C>T) pathogenic?

CUL9 p.Arg1307Trp (c.3919C>T) is classified Uncertain significance in CUL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: ambiguous (0.3776); Very rare (popmax 0.00446%, eas).

How common is CUL9 p.Arg1307Trp (c.3919C>T) in the general population?

CUL9 p.Arg1307Trp (c.3919C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CUL9 p.Arg1307Trp (c.3919C>T)?

AlphaMissense predicts ambiguous (score 0.3776) — an in-silico prediction, not a clinical call.

CUL9 p.Arg1307Trp

c.3919C>T · rs374291463 · VCV2463535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.3776	ambiguous
REVEL	0.498	indeterminate
SaProt	LLR -7.10	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.96 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 36 kb · p 3.2e-27 · regional, not allelic
Overall
CADD	29.8	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

Grpmax group 0.00446% East Asian · 2/44,892 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.0039% 63/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Finnishnot grpmax-eligible	0.00781%	12,803
East Asiangrpmax	0.00446%	22,446
European (non-Finnish)	0.00398%	25,107
South Asian	0.0022%	45,544
African / African-American	0.00133%	75,008

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1307Trp
Coding: c.3919C>T
MANE Select: NM_015089
dbSNP: rs374291463
Type: single nucleotide variant
Location: chr6:43203486 (GRCh38)
Gene constraint: LOEUF 0.334 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.64 · 4 PDB
Residue 1307: an α-helix; the doc domain

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-arg1307trp (accessed [today's date]).

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