Is E2F1 p.Ser121Tyr (c.362C>A) pathogenic?

E2F1 p.Ser121Tyr (c.362C>A) is classified Uncertain significance in E2F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: ambiguous (0.4697); Very rare (popmax 0.000424%, nfe).

How common is E2F1 p.Ser121Tyr (c.362C>A) in the general population?

E2F1 p.Ser121Tyr (c.362C>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about E2F1 p.Ser121Tyr (c.362C>A)?

AlphaMissense predicts ambiguous (score 0.4697) — an in-silico prediction, not a clinical call.

E2F1 p.Ser121Tyr

c.362C>A · VCV3274279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4697	ambiguous
REVEL	0.262	benign-leaning
SaProt	LLR -13.63	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.6, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 6,229 bp · p 1.9e-06 · 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 0.000424% European (non-Finnish) · 5/1,179,710 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,304 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: E2F1
Protein: p.Ser121Tyr
Coding: c.362C>A
MANE Select: NM_005225
Type: single nucleotide variant
Location: chr20:33679965 (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 121: a DNA-binding region; the 'interaction with birc2/c-iap1' region; the 'disordered' region

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

Similar variants

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
RBP3 c.3388+4C>G 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/e2f1-p-ser121tyr (accessed [today's date]).

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