Is E4F1 p.Arg554Cys (c.1660C>T) pathogenic?

E4F1 p.Arg554Cys (c.1660C>T) is classified Uncertain significance in E4F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.7887); Ultra-rare (popmax 0.0176%, mid).

How common is E4F1 p.Arg554Cys (c.1660C>T) in the general population?

E4F1 p.Arg554Cys (c.1660C>T) is ultra-rare (popmax 0.0176%, mid) (gnomAD).

What do computational predictors say about E4F1 p.Arg554Cys (c.1660C>T)?

AlphaMissense predicts likely pathogenic (score 0.7887) — an in-silico prediction, not a clinical call.

E4F1 p.Arg554Cys

c.1660C>T · rs375170561 · VCV3086791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7887	likely pathogenic
REVEL	0.315	indeterminate
SaProt	LLR -12.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0176% Middle Eastern · 1/5,680 alleles

Filtering AF 0.000748% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00028%

Overall 0.00106% 17/1,598,420 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0176%	5,680
East Asian	0.00451%	22,153
Admixed American	0.00342%	29,264
African / African-American	0.00268%	37,348
South Asian	0.00225%	44,386
Finnishnot grpmax-eligible	0.00162%	61,650
Remaining individualsnot grpmax-eligible	0.00162%	61,814
European (non-Finnish)	0.000512%	195,457

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.Arg554Cys
Coding: c.1660C>T
MANE Select: NM_004424
dbSNP: rs375170561
Type: single nucleotide variant
Location: chr16:2234649 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.68
Residue 554: the 'mediates interaction with cdkn2a' region; the 'interaction with bmi1' region; the 'mediates interaction with tp53' region

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

Similar variants

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
E4F1 p.Ala292Thr 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-arg554cys (accessed [today's date]).

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