Is E2F2 p.Ser334Asn (c.1001G>A) pathogenic?

E2F2 p.Ser334Asn (c.1001G>A) is classified Uncertain significance in E2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.0804); Very rare (popmax 0.0023%, sas).

How common is E2F2 p.Ser334Asn (c.1001G>A) in the general population?

E2F2 p.Ser334Asn (c.1001G>A) is very rare (popmax 0.0023%, sas) (gnomAD).

What do computational predictors say about E2F2 p.Ser334Asn (c.1001G>A)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

E2F2 p.Ser334Asn

c.1001G>A · VCV4246109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.67	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 0.98	GERP 0.5, phastCons 0.041
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 0.0011 · regional, not allelic
Overall
CADD	12.8	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 0.0023% South Asian · 2/86,858 alleles

Filtering AF 0.000382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000349% 5/1,433,924 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0023%	43,429
European (non-Finnish)	0.000257%	389,454

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.Ser334Asn
Coding: c.1001G>A
MANE Select: NM_004091
Type: single nucleotide variant
Location: chr1:23516379 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.42 · 1 PDB
Residue 334: the 'disordered' 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-ser334asn (accessed [today's date]).

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