Is CCNE2 p.Phe331Leu (c.993T>A) pathogenic?

CCNE2 p.Phe331Leu (c.993T>A) is classified Uncertain significance in CCNE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: likely pathogenic (0.9839); Absent from gnomAD v4.1.

How common is CCNE2 p.Phe331Leu (c.993T>A) in the general population?

CCNE2 p.Phe331Leu (c.993T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCNE2 p.Phe331Leu (c.993T>A)?

AlphaMissense predicts likely pathogenic (score 0.9839) — an in-silico prediction, not a clinical call.

CCNE2 p.Phe331Leu

c.993T>A · VCV4222081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9839 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9839	likely pathogenic · top 8% in CCNE2
REVEL	0.299	indeterminate
SaProt	LLR -10.67	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 3.1	GERP 0.73, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 13 kb · p 8.7e-06 · regional, not allelic
Overall
CADD	23.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCNE2
Protein: p.Phe331Leu
Coding: c.993T>A
MANE Select: NM_057749
Type: single nucleotide variant
Location: chr8:94882240 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 77.80 · 1 PDB

Full CCNE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCNE2 p.Ala204Gly Uncertain significance ★ ⚠ same type
CCNE2 p.Asp222Gly Uncertain significance ★ ⚠ same type
CCNE2 p.Asp258Gly Uncertain significance ★ ⚠ same type
CCNE2 p.Glu221Lys Uncertain significance ★ ⚠ same type
CCNE2 p.Glu323Gln Uncertain significance ★ ⚠ same type
CCNE2 p.Glu323Val Uncertain significance ★ ⚠ same type
CCNE2 p.Gly402Arg Uncertain significance ★ ⚠ same type
CCNE2 p.His159Tyr 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/ccne2-p-phe331leu (accessed [today's date]).

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