Is CCNB2 p.Leu218Phe (c.654G>C) pathogenic?

CCNB2 p.Leu218Phe (c.654G>C) is classified Uncertain significance in CCNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-18). AlphaMissense: likely pathogenic (0.7112); Very rare (popmax 0.00223%, eas).

How common is CCNB2 p.Leu218Phe (c.654G>C) in the general population?

CCNB2 p.Leu218Phe (c.654G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCNB2 p.Leu218Phe (c.654G>C)?

AlphaMissense predicts likely pathogenic (score 0.7112) — an in-silico prediction, not a clinical call.

CCNB2 p.Leu218Phe

c.654G>C · rs1434276500 · VCV2259795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7112	likely pathogenic
REVEL	0.37	indeterminate
SaProt	LLR -12.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 20 kb · p 0.94 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.0013% 21/1,613,066 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,388
European (non-Finnish)	0.00153%	65,556

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: CCNB2
Protein: p.Leu218Phe
Coding: c.654G>C
MANE Select: NM_004701
dbSNP: rs1434276500
Type: single nucleotide variant
Location: chr15:59116746 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.14

Full CCNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCNB2 p.Ile395Thr Benign ★★ same type
CCNB2 p.Lys89= Benign ★★ same type
CCNB2 p.Met100Thr Benign ★★ same type
CCNB2 p.Ala112Gly Uncertain significance ★ ⚠ same type
CCNB2 p.Ala167Thr Uncertain significance ★ ⚠ same type
CCNB2 p.Ala46Thr Uncertain significance ★ ⚠ same type
CCNB2 p.Arg164Cys Uncertain significance ★ ⚠ same type
CCNB2 p.Arg164His 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/ccnb2-p-leu218phe (accessed [today's date]).

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