Is E2F1 p.Ile400Phe (c.1198A>T) pathogenic?

E2F1 p.Ile400Phe (c.1198A>T) is classified Uncertain significance in E2F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.3383); Very rare (popmax 0.00113%, sas).

How common is E2F1 p.Ile400Phe (c.1198A>T) in the general population?

E2F1 p.Ile400Phe (c.1198A>T) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about E2F1 p.Ile400Phe (c.1198A>T)?

AlphaMissense predicts likely benign (score 0.3383) — an in-silico prediction, not a clinical call.

E2F1 p.Ile400Phe

c.1198A>T · VCV4015801

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3383 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3383	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -3.95	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 6.2	GERP 6.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 533 bp · p 0.17 · regional, not allelic
Overall
CADD	25.1	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 0.00113% South Asian · 1/88,204 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000251% 4/1,592,142 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00113%	88,204
European (non-Finnish)	0.000257%	389,510

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: E2F1
Protein: p.Ile400Phe
Coding: c.1198A>T
MANE Select: NM_005225
Type: single nucleotide variant
Location: chr20:33676848 (GRCh38)
Gene constraint: LOEUF 0.399 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 63.40 · 8 PDB
Residue 400: the 'transactivation' region

Full E2F1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RBP3 p.Ala400= Uncertain significance ★ same residue
RBP3 p.Ala400Val Conflicting classifications of pathogenicity ★ ⚠ same residue
RBP3 p.Arg388Ter Pathogenic ★★ same type
RBP3 p.Gln141Ter Pathogenic/Likely pathogenic ★★ same type
RBP3 p.Gln54Ter Pathogenic ★★ same type
RBP3 p.Glu149Ter Pathogenic ★★ same type
RBP3 p.Glu692Ter Pathogenic/Likely pathogenic ★★ same type
RBP3 p.Tyr784Ter Pathogenic/Likely pathogenic ★★ 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/e2f1-p-ile400phe (accessed [today's date]).

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