Is EIF4E2 p.Arg241Trp (c.721C>T) pathogenic?

EIF4E2 p.Arg241Trp (c.721C>T) is classified Uncertain significance in EIF4E2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.4165); Ultra-rare (popmax 0.0252%, nfe).

How common is EIF4E2 p.Arg241Trp (c.721C>T) in the general population?

EIF4E2 p.Arg241Trp (c.721C>T) is ultra-rare (popmax 0.0252%, nfe) (gnomAD).

What do computational predictors say about EIF4E2 p.Arg241Trp (c.721C>T)?

AlphaMissense predicts ambiguous (score 0.4165) — an in-silico prediction, not a clinical call.

EIF4E2 p.Arg241Trp

c.721C>T · rs146216550 · VCV2461277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4165 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4165	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -6.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.3, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 64 bp · p 0.47 · regional, not allelic
Overall
CADD	24.3	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 0.0252% European (non-Finnish) · 297/1,180,030 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.0204% 329/1,614,168 alleles · ultra-rare exomes 294/1,461,844 · genomes 35/152,324 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0252%	3,973
Admixed American	0.015%	6,669
South Asian	0.0132%	7,589
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Finnishnot grpmax-eligible	0.00468%	21,346
African / African-American	0.004%	25,015
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: EIF4E2
Protein: p.Arg241Trp
Coding: c.721C>T
MANE Select: NM_004846
dbSNP: rs146216550
Type: single nucleotide variant
Location: chr2:232569000 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 80.42 · 7 PDB

Full EIF4E2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF4E2 p.Arg241Gln Uncertain significance ★ ⚠ same residue
EIF4E2 p.Ala7Thr Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg103His Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg146His Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg174Cys Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg197Gln Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg197Trp Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg231Gly 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/eif4e2-p-arg241trp (accessed [today's date]).

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