Is E2F4 p.Ser75Thr (c.223T>A) pathogenic?

E2F4 p.Ser75Thr (c.223T>A) is classified Uncertain significance in E2F4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely pathogenic (0.856); Very rare (popmax 0.00204%, nfe).

How common is E2F4 p.Ser75Thr (c.223T>A) in the general population?

E2F4 p.Ser75Thr (c.223T>A) is very rare (popmax 0.00204%, nfe) (gnomAD).

What do computational predictors say about E2F4 p.Ser75Thr (c.223T>A)?

AlphaMissense predicts likely pathogenic (score 0.856) — an in-silico prediction, not a clinical call.

E2F4 p.Ser75Thr

c.223T>A · VCV3843181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00204%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.856	likely pathogenic
REVEL	0.619	indeterminate
SaProt	LLR -10.01	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 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 2,127 bp · p 1.9e-05 · regional, not allelic
Overall
CADD	25.2	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

Grpmax group 0.00204% European (non-Finnish) · 24/1,179,092 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00155% 25/1,612,094 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00204%	49,129
Admixed American	0.00168%	59,692

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.Ser75Thr
Coding: c.223T>A
MANE Select: NM_001950
Type: single nucleotide variant
Location: chr16:67192848 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 65.56 · 2 PDB
Residue 75: 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-ser75thr (accessed [today's date]).

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