Is CUL2 p.Phe211Leu (c.631T>C) pathogenic?

CUL2 p.Phe211Leu (c.631T>C) is classified Uncertain significance in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.9459); Very rare (popmax 0.00534%, afr).

How common is CUL2 p.Phe211Leu (c.631T>C) in the general population?

CUL2 p.Phe211Leu (c.631T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CUL2 p.Phe211Leu (c.631T>C)?

AlphaMissense predicts likely pathogenic (score 0.9459) — an in-silico prediction, not a clinical call.

CUL2 p.Phe211Leu

c.631T>C · VCV3837440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9459	likely pathogenic
REVEL	0.439	indeterminate
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	acceptor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 38 kb · p 6.8e-07 · regional, not allelic
Overall
CADD	23.7	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 0.00534% African / African-American · 4/74,902 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000823% 12/1,457,358 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00803%	12,457
African / African-Americangrpmax	0.00534%	18,726
European (non-Finnish)	0.000254%	392,986

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: CUL2
Protein: p.Phe211Leu
Coding: c.631T>C
MANE Select: NM_003591
Type: single nucleotide variant
Location: chr10:35044649 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 42 PDB
Residue 211: 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-phe211leu (accessed [today's date]).

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