Is CUL2 p.Val24Met (c.70G>A) pathogenic?

CUL2 p.Val24Met (c.70G>A) is classified Uncertain significance in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9653); Very rare (popmax 0.00223%, eas).

How common is CUL2 p.Val24Met (c.70G>A) in the general population?

CUL2 p.Val24Met (c.70G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CUL2 p.Val24Met (c.70G>A)?

AlphaMissense predicts likely pathogenic (score 0.9653) — an in-silico prediction, not a clinical call.

CUL2 p.Val24Met

c.70G>A · VCV4236076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9653	likely pathogenic
REVEL	0.36	indeterminate
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 6.8e-07 · 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 0.00223% East Asian · 1/44,874 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00161% 26/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
South Asian	0.0022%	45,538
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Val24Met
Coding: c.70G>A
MANE Select: NM_003591
Type: single nucleotide variant
Location: chr10:35071248 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 42 PDB
Residue 24: an α-helix

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

Similar variants

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
CUL2 p.Ala671Ser 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-val24met (accessed [today's date]).

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