Is CCNB3 p.Ser449Phe (c.1346C>T) pathogenic?

CCNB3 p.Ser449Phe (c.1346C>T) is classified Uncertain significance in CCNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.1929); Very rare (popmax 0.00591%, eas).

How common is CCNB3 p.Ser449Phe (c.1346C>T) in the general population?

CCNB3 p.Ser449Phe (c.1346C>T) is very rare (popmax 0.00591%, eas) (gnomAD).

What do computational predictors say about CCNB3 p.Ser449Phe (c.1346C>T)?

AlphaMissense predicts likely benign (score 0.1929) — an in-silico prediction, not a clinical call.

CCNB3 p.Ser449Phe

c.1346C>T · rs782534876 · VCV2547922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00591%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1929	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -8.61	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 -0.36	GERP -2.1
Regional constraint	o/e 1.02	unconstrained · MANE · 26 kb · p 0.71 · regional, not allelic
Overall
CADD	10.25	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 0.00591% East Asian · 2/33,822 alleles

Filtering AF 0.000979% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000182% 2/1,098,121 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: CCNB3
Protein: p.Ser449Phe
Coding: c.1346C>T
MANE Select: NM_033031
dbSNP: rs782534876
Type: single nucleotide variant
Location: chrX:50309515 (GRCh38)
Structure: AlphaFold pLDDT 42.25
Residue 449: the 'disordered' region

Full CCNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCNB3 p.Ala702= Benign ★★ same type
CCNB3 p.Gly1001Arg Benign ★★ same type
CCNB3 p.Lys857Gln Likely benign ★★ ⚠ same type
CCNB3 p.Ser188Thr Benign ★★ ⚠ same type
CCNB3 p.Ala1208Thr Uncertain significance ★ ⚠ same type
CCNB3 p.Ala312Pro Uncertain significance ★ ⚠ same type
CCNB3 p.Ala437Ser Uncertain significance ★ ⚠ same type
CCNB3 p.Ala981Thr 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/ccnb3-p-ser449phe (accessed [today's date]).

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