Is E2F2 p.Phe403Cys (c.1208T>G) pathogenic?

E2F2 p.Phe403Cys (c.1208T>G) is classified Uncertain significance in E2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely pathogenic (0.693); Ultra-rare (popmax 0.0429%, nfe).

How common is E2F2 p.Phe403Cys (c.1208T>G) in the general population?

E2F2 p.Phe403Cys (c.1208T>G) is ultra-rare (popmax 0.0429%, nfe) (gnomAD).

What do computational predictors say about E2F2 p.Phe403Cys (c.1208T>G)?

AlphaMissense predicts likely pathogenic (score 0.693) — an in-silico prediction, not a clinical call.

E2F2 p.Phe403Cys

c.1208T>G · rs142571891 · VCV2347985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0429%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.693	likely pathogenic
REVEL	0.41	indeterminate
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 0.0011 · regional, not allelic
Overall
CADD	28.6	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 0.0429% European (non-Finnish) · 506/1,179,746 alleles

Filtering AF 0.0398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0358% 577/1,613,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0516%	1,940
European (non-Finnish)grpmax	0.0429%	2,332
Remaining individualsnot grpmax-eligible	0.0352%	2,839
Admixed American	0.0217%	4,608
African / African-American	0.00401%	24,951

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe403Cys
Coding: c.1208T>G
MANE Select: NM_004091
dbSNP: rs142571891
Type: single nucleotide variant
Location: chr1:23509986 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.42 · 1 PDB
Residue 403: the 'transactivation' 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-phe403cys (accessed [today's date]).

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