Is E2F4 p.Pro15Arg (c.44C>G) pathogenic?

E2F4 p.Pro15Arg (c.44C>G) is classified Uncertain significance in E2F4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely pathogenic (0.8639); Very rare (popmax 0.00029%, nfe).

How common is E2F4 p.Pro15Arg (c.44C>G) in the general population?

E2F4 p.Pro15Arg (c.44C>G) is very rare (popmax 0.00029%, nfe) (gnomAD).

What do computational predictors say about E2F4 p.Pro15Arg (c.44C>G)?

AlphaMissense predicts likely pathogenic (score 0.8639) — an in-silico prediction, not a clinical call.

E2F4 p.Pro15Arg

c.44C>G · rs1382714278 · VCV2265533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00029%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8639	likely pathogenic
REVEL	0.198	benign-leaning
SaProt	LLR -12.99	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 62 bp · p 0.099 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00029% European (non-Finnish) · 3/1,033,432 alleles

Filtering AF 7.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000256% 3/1,172,552 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: E2F4
Protein: p.Pro15Arg
Coding: c.44C>G
MANE Select: NM_001950
dbSNP: rs1382714278
Type: single nucleotide variant
Location: chr16:67192271 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 65.56 · 2 PDB
Residue 15: the 'disordered' region

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

Similar variants

E2F4 p.Pro15Leu Uncertain significance ★ ⚠ same residue
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

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-pro15arg (accessed [today's date]).

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