Is E2F3 p.Arg121Cys (c.361C>T) pathogenic?

E2F3 p.Arg121Cys (c.361C>T) is classified Uncertain significance in E2F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.3274); Very rare (popmax 0.0076%, afr).

How common is E2F3 p.Arg121Cys (c.361C>T) in the general population?

E2F3 p.Arg121Cys (c.361C>T) is very rare (popmax 0.0076%, afr) (gnomAD).

What do computational predictors say about E2F3 p.Arg121Cys (c.361C>T)?

AlphaMissense predicts likely benign (score 0.3274) — an in-silico prediction, not a clinical call.

E2F3 p.Arg121Cys

c.361C>T · VCV4662776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0076%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3274	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -6.80	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 5.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 79 kb · p 0.9 · regional, not allelic
Overall
CADD	23.0	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 0.0076% African / African-American · 5/65,806 alleles

Filtering AF 0.00292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.000652% 9/1,381,280 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0076%	13,161
European (non-Finnish)	0.000372%	269,067

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: E2F3
Protein: p.Arg121Cys
Coding: c.361C>T
MANE Select: NM_001949
Type: single nucleotide variant
Location: chr6:20402593 (GRCh38)
Gene constraint: LOEUF 0.393 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.16
Residue 121: the 'disordered' region; the 'cyclin a/cdk2 binding' region

Full E2F3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F3 p.Asp389Asn Benign ★★ same type
E2F3 p.Ala404Ser Uncertain significance ★ ⚠ same type
E2F3 p.Ala450Gly Uncertain significance ★ ⚠ same type
E2F3 p.Ala8Ser Uncertain significance ★ ⚠ same type
E2F3 p.Arg305Gln Uncertain significance ★ ⚠ same type
E2F3 p.Asn369Asp Uncertain significance ★ ⚠ same type
E2F3 p.Asn396His Uncertain significance ★ ⚠ same type
E2F3 p.Asn424Asp 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/e2f3-p-arg121cys (accessed [today's date]).

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