Is CUL2 p.Arg70Trp (c.208C>T) pathogenic?

CUL2 p.Arg70Trp (c.208C>T) is classified Uncertain significance in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.158); Ultra-rare (popmax 0.0179%, eas).

How common is CUL2 p.Arg70Trp (c.208C>T) in the general population?

CUL2 p.Arg70Trp (c.208C>T) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about CUL2 p.Arg70Trp (c.208C>T)?

AlphaMissense predicts likely benign (score 0.158) — an in-silico prediction, not a clinical call.

CUL2 p.Arg70Trp

c.208C>T · rs754713861 · VCV2458941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.158	likely benign
REVEL	0.47	indeterminate
SaProt	LLR -11.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.45	donor loss, 14 bp away · masked 0 · deltas
Pangolin	Δ0.33	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 6.8e-07 · regional, not allelic
Overall
CADD	28.4	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 0.0179% East Asian · 8/44,724 alleles

Filtering AF 0.00935% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00878%

Overall 0.0093% 148/1,591,552 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,590
European (non-Finnish)	0.0109%	9,135
South Asian	0.00664%	15,069
African / African-American	0.00538%	18,586
Remaining individualsnot grpmax-eligible	0.00324%	30,868
Admixed American	0.00167%	59,792

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.Arg70Trp
Coding: c.208C>T
MANE Select: NM_003591
dbSNP: rs754713861
Type: single nucleotide variant
Location: chr10:35062974 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 42 PDB
Residue 70: an α-helix

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

Similar variants

CUL2 p.Arg70Gln 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-arg70trp (accessed [today's date]).

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