Is CUL2 p.Ser656Pro (c.1966T>C) pathogenic?

CUL2 p.Ser656Pro (c.1966T>C) is classified Uncertain significance in CUL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.3329); Very rare (popmax 0.00814%, afr).

How common is CUL2 p.Ser656Pro (c.1966T>C) in the general population?

CUL2 p.Ser656Pro (c.1966T>C) is very rare (popmax 0.00814%, afr) (gnomAD).

What do computational predictors say about CUL2 p.Ser656Pro (c.1966T>C)?

AlphaMissense predicts likely benign (score 0.3329) — an in-silico prediction, not a clinical call.

CUL2 p.Ser656Pro

c.1966T>C · VCV4236080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00814%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3329	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -5.21	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 9.3	GERP 1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 6,019 bp · p 0.0021 · regional, not allelic
Overall
CADD	24.0	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 0.00814% African / African-American · 6/73,708 alleles

Filtering AF 0.00352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000383% 6/1,567,678 alleles · very rare

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.Ser656Pro
Coding: c.1966T>C
MANE Select: NM_003591
Type: single nucleotide variant
Location: chr10:35013722 (GRCh38)
Gene constraint: LOEUF 0.305 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 42 PDB
Residue 656: a turn

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-ser656pro (accessed [today's date]).

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