Is E2F2 p.Arg256Cys (c.766C>T) pathogenic?

E2F2 p.Arg256Cys (c.766C>T) is classified Uncertain significance in E2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.3324); Ultra-rare (popmax 0.0165%, mid).

How common is E2F2 p.Arg256Cys (c.766C>T) in the general population?

E2F2 p.Arg256Cys (c.766C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about E2F2 p.Arg256Cys (c.766C>T)?

AlphaMissense predicts likely benign (score 0.3324) — an in-silico prediction, not a clinical call.

E2F2 p.Arg256Cys

c.766C>T · VCV4662764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3324 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3324	likely benign
REVEL	0.683	pathogenic-leaning
SaProt	LLR -9.89	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 0.0011 · regional, not allelic
Overall
CADD	34.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00155% 25/1,613,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
African / African-American	0.00267%	37,522
East Asian	0.00223%	44,870
South Asian	0.0022%	45,503
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)	0.00153%	65,548

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: E2F2
Protein: p.Arg256Cys
Coding: c.766C>T
MANE Select: NM_004091
Type: single nucleotide variant
Location: chr1:23519102 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.42 · 1 PDB
Residue 256: the 'dimerization' region

Full E2F2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F2 p.Pro310Leu Benign ★★ same type
E2F2 p.Thr202Ile Likely benign ★★ ⚠ same type
E2F2 p.Ala158Thr Uncertain significance ★ ⚠ same type
E2F2 p.Ala21Val Uncertain significance ★ ⚠ same type
E2F2 p.Ala223Val Uncertain significance ★ ⚠ same type
E2F2 p.Ala395Val Uncertain significance ★ ⚠ same type
E2F2 p.Ala40Gly Uncertain significance ★ ⚠ same type
E2F2 p.Ala40Val 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/e2f2-p-arg256cys (accessed [today's date]).

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