Is CUL2 p.Val299Ile (c.895G>A) pathogenic?

CUL2 p.Val299Ile (c.895G>A) is classified Uncertain significance in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.0752); Ultra-rare (popmax 0.0582%, sas).

How common is CUL2 p.Val299Ile (c.895G>A) in the general population?

CUL2 p.Val299Ile (c.895G>A) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

What do computational predictors say about CUL2 p.Val299Ile (c.895G>A)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

CUL2 p.Val299Ile

c.895G>A · VCV3498615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -6.41	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 3.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 6.8e-07 · regional, not allelic
Overall
CADD	21.0	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 0.0582% South Asian · 53/91,056 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.00607% 98/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,718
Middle Eastern	0.0165%	6,062
Admixed American	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.008%	12,500
African / African-American	0.00267%	37,502
European (non-Finnish)	0.00263%	38,062
East Asian	0.00223%	44,872

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: CUL2
Protein: p.Val299Ile
Coding: c.895G>A
MANE Select: NM_003591
Type: single nucleotide variant
Location: chr10:35035279 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 42 PDB
Residue 299: an α-helix

Full CUL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CUL2 p.Val299Ala Uncertain significance ★ ⚠ same residue
CUL2 p.Arg148= Benign ★★ same type
CUL2 c.1110+1G>A Uncertain significance ★ same type
CUL2 c.-22-2881A>G Uncertain significance ★ same type
CUL2 c.-2C>A Uncertain significance ★ same type
CUL2 p.Ala403Val Uncertain significance ★ ⚠ same type
CUL2 p.Ala522Val Uncertain significance ★ ⚠ same type
CUL2 p.Ala634Ser 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/cul2-p-val299ile (accessed [today's date]).

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