Is CUL2 p.His71Tyr (c.211C>T) pathogenic?

CUL2 p.His71Tyr (c.211C>T) is classified Uncertain significance in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: likely benign (0.0823); Very rare (popmax 0.00448%, eas).

How common is CUL2 p.His71Tyr (c.211C>T) in the general population?

CUL2 p.His71Tyr (c.211C>T) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about CUL2 p.His71Tyr (c.211C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

CUL2 p.His71Tyr

c.211C>T · rs749400273 · VCV2489524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.40	donor loss, 11 bp away · masked 0 · deltas
Pangolin	Δ0.24	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 6.8e-07 · regional, not allelic
Overall
CADD	23.0	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 0.00448% East Asian · 2/44,688 alleles

Filtering AF 0.000742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000374%

Overall 0.000947% 15/1,583,244 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00448%	22,344
Remaining individualsnot grpmax-eligible	0.00325%	30,744
European (non-Finnish)	0.000954%	104,774

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.His71Tyr
Coding: c.211C>T
MANE Select: NM_003591
dbSNP: rs749400273
Type: single nucleotide variant
Location: chr10:35062971 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 42 PDB
Residue 71: 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-his71tyr (accessed [today's date]).

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