Is E2F1 p.Arg166His (c.497G>A) pathogenic?

E2F1 p.Arg166His (c.497G>A) is classified Uncertain significance in E2F1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9956); No allele count reported in gnomAD v4.1 (AN 1,614,210); Associated with prostate cancer.

What condition is associated with E2F1 p.Arg166His (c.497G>A)?

E2F1 p.Arg166His (c.497G>A) is associated with prostate cancer (ClinVar).

How common is E2F1 p.Arg166His (c.497G>A) in the general population?

E2F1 p.Arg166His (c.497G>A) is no allele count reported in gnomAD v4.1 (AN 1,614,210) (gnomAD).

What do computational predictors say about E2F1 p.Arg166His (c.497G>A)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

E2F1 p.Arg166His

c.497G>A · rs864622017 · VCV219310

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,210)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

prostate cancer

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic · top 5% in E2F1
REVEL	0.755	pathogenic-leaning
SaProt	LLR -13.84	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 7.7	GERP 6.6, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 1,496 bp · p 7.7e-09 · regional, not allelic
Overall
CADD	33.0	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

No allele count reported in gnomAD v4.1 (AN 1,614,210). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: E2F1
Protein: p.Arg166His
Coding: c.497G>A
MANE Select: NM_005225
dbSNP: rs864622017
Type: single nucleotide variant
Location: chr20:33679830 (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 166: a DNA-binding region; the 'interaction with birc2/c-iap1' region; the 'leucine-zipper' region

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

Disease context

prostate cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RBP3 p.Val166= Likely benign ★ 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
RBP3 p.Tyr841Ter 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-arg166his (accessed [today's date]).

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