Is EIF4E p.Arg181Met (c.542G>T) pathogenic?

EIF4E p.Arg181Met (c.542G>T) is classified Uncertain significance in EIF4E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: ambiguous (0.4354); Very rare (popmax 0.00645%, nfe).

How common is EIF4E p.Arg181Met (c.542G>T) in the general population?

EIF4E p.Arg181Met (c.542G>T) is very rare (popmax 0.00645%, nfe) (gnomAD).

What do computational predictors say about EIF4E p.Arg181Met (c.542G>T)?

AlphaMissense predicts ambiguous (score 0.4354) — an in-silico prediction, not a clinical call.

EIF4E p.Arg181Met

c.542G>T · VCV3275034

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4354 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00645%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4354	ambiguous
REVEL	0.298	indeterminate
SaProt	LLR -13.00	damaging
Splicing
SpliceAI	Δ0.33	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.2	GERP 1, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 21 kb · p 1.6e-23 · regional, not allelic
Overall
CADD	23.8	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 0.00645% European (non-Finnish) · 76/1,178,928 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00504% 81/1,608,640 alleles · very rare exomes 79/1,459,346 · genomes 2/149,294 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00645%	15,512
Remaining individualsnot grpmax-eligible	0.00481%	20,779
Finnishnot grpmax-eligible	0.00158%	63,396
African / African-American	0.00137%	72,862

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: EIF4E
Protein: p.Arg181Met
Coding: c.542G>T
MANE Select: NM_001968
Type: single nucleotide variant
Location: chr4:98881140 (GRCh38)
Gene constraint: LOEUF 0.09 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.48 · 45 PDB
Residue 181: an α-helix

Full EIF4E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF4E c.18+1G>T Uncertain significance ★ same type
EIF4E c.399+599C>T Uncertain significance ★ same type
EIF4E p.Ala29Thr Uncertain significance ★ ⚠ same type
EIF4E p.Arg109Leu Uncertain significance ★ ⚠ same type
EIF4E p.Asn41Ser Uncertain significance ★ ⚠ same type
EIF4E p.Glu5Lys Uncertain significance ★ ⚠ same type
EIF4E p.Gly196Ser Uncertain significance ★ ⚠ same type
EIF4E p.His33Arg 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/eif4e-p-arg181met (accessed [today's date]).

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