Is E2F4 p.Ala2Gly (c.5C>G) pathogenic?

E2F4 p.Ala2Gly (c.5C>G) is classified Uncertain significance in E2F4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: likely benign (0.184); Ultra-rare (popmax 0.033%, eas).

How common is E2F4 p.Ala2Gly (c.5C>G) in the general population?

E2F4 p.Ala2Gly (c.5C>G) is ultra-rare (popmax 0.033%, eas) (gnomAD).

What do computational predictors say about E2F4 p.Ala2Gly (c.5C>G)?

AlphaMissense predicts likely benign (score 0.184) — an in-silico prediction, not a clinical call.

E2F4 p.Ala2Gly

c.5C>G · rs755790677 · VCV2610640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.184	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -8.88	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 7.5	GERP 0.91, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 62 bp · p 0.099 · regional, not allelic
Overall
CADD	26.9	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 0.033% East Asian · 8/24,222 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.000875% 10/1,142,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.033%	3,028
Remaining individualsnot grpmax-eligible	0.00259%	38,658
European (non-Finnish)	0.000108%	927,085

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.Ala2Gly
Coding: c.5C>G
MANE Select: NM_001950
dbSNP: rs755790677
Type: single nucleotide variant
Location: chr16:67192232 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 65.56 · 2 PDB
Residue 2: a modified residue (n-acetylalanine); the 'disordered' region

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.Ala340Ser Uncertain significance ★ ⚠ same type
E2F4 p.Ala4Pro Uncertain significance ★ ⚠ same type
E2F4 p.Arg126Gln Uncertain significance ★ ⚠ same type
E2F4 p.Arg241Cys 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-ala2gly (accessed [today's date]).

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