Is E4F1 p.Arg487Cys (c.1459C>T) pathogenic?

E4F1 p.Arg487Cys (c.1459C>T) is classified Uncertain significance in E4F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.3977); Very rare (popmax 0.0022%, sas).

How common is E4F1 p.Arg487Cys (c.1459C>T) in the general population?

E4F1 p.Arg487Cys (c.1459C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about E4F1 p.Arg487Cys (c.1459C>T)?

AlphaMissense predicts ambiguous (score 0.3977) — an in-silico prediction, not a clinical call.

E4F1 p.Arg487Cys

c.1459C>T · VCV4662832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3977	ambiguous
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,400 bp · p 0.81 · regional, not allelic
Overall
CADD	25.4	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 0.0022% South Asian · 2/91,092 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000616% 9/1,460,520 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,546
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000508%	196,660

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: E4F1
Protein: p.Arg487Cys
Coding: c.1459C>T
MANE Select: NM_004424
Type: single nucleotide variant
Location: chr16:2234254 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.68
Residue 487: the 'mediates interaction with cdkn2a' region; the 'interaction with bmi1' region

Full E4F1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E4F1 p.Arg487Pro Uncertain significance ★ ⚠ same residue
E4F1 p.Arg490His Uncertain significance ★★ ⚠ same type
E4F1 p.Lys144Gln Likely pathogenic ★ ⚠ same type
E4F1 p.Ala124Val Uncertain significance ★ ⚠ same type
E4F1 p.Ala152Val Uncertain significance ★ ⚠ same type
E4F1 p.Ala15Thr Uncertain significance ★ ⚠ same type
E4F1 p.Ala21Asp Uncertain significance ★ ⚠ same type
E4F1 p.Ala21Ser 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/e4f1-p-arg487cys (accessed [today's date]).

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