Is E2F4 p.Lys74Asn (c.222G>C) pathogenic?

E2F4 p.Lys74Asn (c.222G>C) is classified Uncertain significance in E2F4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1.

How common is E2F4 p.Lys74Asn (c.222G>C) in the general population?

E2F4 p.Lys74Asn (c.222G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about E2F4 p.Lys74Asn (c.222G>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

E2F4 p.Lys74Asn

c.222G>C · VCV3843182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 8% in E2F4
REVEL	0.703	pathogenic-leaning
SaProt	LLR -13.43	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 1.6	GERP -2.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 2,127 bp · p 1.9e-05 · regional, not allelic
Overall
CADD	21.7	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: E2F4
Protein: p.Lys74Asn
Coding: c.222G>C
MANE Select: NM_001950
Type: single nucleotide variant
Location: chr16:67192847 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 65.56 · 2 PDB
Residue 74: a DNA-binding region; a β-strand

Full E2F4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F4 p.Ala138Val Uncertain significance ★ ⚠ same type
E2F4 p.Ala150Thr Uncertain significance ★ ⚠ same type
E2F4 p.Ala239Gly Uncertain significance ★ ⚠ same type
E2F4 p.Ala239Pro Uncertain significance ★ ⚠ same type
E2F4 p.Ala2Gly Uncertain significance ★ ⚠ same type
E2F4 p.Ala340Ser Uncertain significance ★ ⚠ same type
E2F4 p.Ala4Pro Uncertain significance ★ ⚠ same type
E2F4 p.Arg126Gln 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/e2f4-p-lys74asn (accessed [today's date]).

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