Is E2F2 p.Lys270Glu (c.808A>G) pathogenic?

E2F2 p.Lys270Glu (c.808A>G) is classified Uncertain significance in E2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.9469); Very rare (popmax 0.00333%, amr).

How common is E2F2 p.Lys270Glu (c.808A>G) in the general population?

E2F2 p.Lys270Glu (c.808A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about E2F2 p.Lys270Glu (c.808A>G)?

AlphaMissense predicts likely pathogenic (score 0.9469) — an in-silico prediction, not a clinical call.

E2F2 p.Lys270Glu

c.808A>G · VCV4246105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9469	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -14.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 0.0011 · regional, not allelic
Overall
CADD	25.3	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 0.00333% Admixed American · 2/59,980 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,990
African / African-American	0.00267%	37,461
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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: E2F2
Protein: p.Lys270Glu
Coding: c.808A>G
MANE Select: NM_004091
Type: single nucleotide variant
Location: chr1:23519060 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.42 · 1 PDB
Residue 270: the 'dimerization' region

Full E2F2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F2 p.Pro310Leu Benign ★★ same type
E2F2 p.Thr202Ile Likely benign ★★ ⚠ same type
E2F2 p.Ala158Thr Uncertain significance ★ ⚠ same type
E2F2 p.Ala21Val Uncertain significance ★ ⚠ same type
E2F2 p.Ala223Val Uncertain significance ★ ⚠ same type
E2F2 p.Ala395Val Uncertain significance ★ ⚠ same type
E2F2 p.Ala40Gly Uncertain significance ★ ⚠ same type
E2F2 p.Ala40Val 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/e2f2-p-lys270glu (accessed [today's date]).

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