Is E4F1 p.Arg490His (c.1469G>A) pathogenic?

E4F1 p.Arg490His (c.1469G>A) is classified Uncertain significance in E4F1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). AlphaMissense: ambiguous (0.5638); Ultra-rare (popmax 0.0351%, sas).

How common is E4F1 p.Arg490His (c.1469G>A) in the general population?

E4F1 p.Arg490His (c.1469G>A) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

What do computational predictors say about E4F1 p.Arg490His (c.1469G>A)?

AlphaMissense predicts ambiguous (score 0.5638) — an in-silico prediction, not a clinical call.

E4F1 p.Arg490His

c.1469G>A · rs767398028 · VCV2511110

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5638	ambiguous
REVEL	0.209	benign-leaning
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,400 bp · p 0.81 · regional, not allelic
Overall
CADD	32.0	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 0.0351% South Asian · 32/91,096 alleles

Filtering AF 0.0255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00316% 51/1,612,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,847
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0064%	15,617
Admixed American	0.00333%	29,996
European (non-Finnish)	0.000678%	147,498

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.Arg490His
Coding: c.1469G>A
MANE Select: NM_004424
dbSNP: rs767398028
Type: single nucleotide variant
Location: chr16:2234264 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.68
Residue 490: 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.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
E4F1 p.Ala292Thr Uncertain significance ★ ⚠ same type
E4F1 p.Ala29Val 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-arg490his (accessed [today's date]).

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